1 3-diaza-2 3-cycloalkene derivatives

ABSTRACT

2-(A-(LOWER-ALKOXY) BENZYL) -2-IMIDZOLINES,-1,4,5,6TETRAHYDROPYRIMIDINES AND -4,5,6,7-TETRAHYDRO-1H-1,3-DIAZEPINES, HAVING PHARMACOLOGICAL PROPERTIES, E.G., HYPOGLYCEMIC, DIURETIC, ANTI-INFLAMMATORY, ARE PREPARED BY HEATING A 2-(LOWER-ALKOXY)-2-PHENYLALKANENITRILE WITH AN ALKANEDIAMINE, WHEREIN 2,3 OR 4 CARBON ATOMS, RESPECTIVELY INTERVENE BETWEEN THE TWO AMINO GROUPS, IN THE PRESENCE OF A CATALYTIC AMOUNT OF CARBON DISULFIDE OR HYDROGEN SULFIDE. THE INTERMEDIATE 2-(LOWER-ALKOXY)-2PHENYLALKANENITRILES ARE PREPARED PREFERABLY BY FIRST REACTING A BENZALDEHYDE WITH A TRI-(LOWER-ALKYL) ORTHOFORMATE TO FORM THE ALDEHYDE DI-(LOWER-ALKYL) ACETAL, REACTING THE LATTER WITH AN ACYL HALIDE TO FORM THE CORRESPONDING AHALOBENZYL LOWER-ALKYL ETHER AND REACTING SAID ETHER WITH AN ALKALI CYANIDE TO YIELD SAID INTERMEDIATE NITRILE.

nit-ed States Patent 5563 3,657,229 Patented Apr. 18, 1972 3,657,2291,3-DIAZA-2,3-CYCLOALKENE DERIVATIVES Denis M. Bailey, Greenbush, N.Y.,assignor to Sterling Drug 1116., New York, N.Y.

No Drawing. Filed May 2, 1968, Ser. No. 726,212 Int. Cl. C07d 53/02,51/28, 49/34 US. Cl. 260-239 BC Claims ABSTRACT OF THE DISCLOSURE 2[a-(lower-alkoxy)benzyl] 2 imidazolines, -1,4,5,6- tetrahydropyrimidinesand -4,5,6,7-tetrahydro-1H-1,3-diazepines, having pharmacologicalproperties, e.g., hypoglycemic, diuretic, anti-inflammatory, areprepared by heating a 2-(lower-alkoxy)-2-phenylalkanenitrile With analkanediamine, wherein 2, 3 or 4 carbon atoms, respectively intervenebetween the two amino groups, in the presence of a catalytic amount ofcarbon disulfide or hydrogen sulfide. The intermediate2-(lower-alkoxy)-2- phenylalkanenitriles are prepared preferably byfirst reacting a benzaldehyde with a tri-(lower-alkyl) orthoformate toform the aldehyde di-(lower-alkyl) acetal, reacting the latter with anacyl halide to form the corresponding uhalobenzyl loWer-alkyl ether andreacting said ether with an alkali cyanide to yield said intermediatenitrile.

This invention relates to compositions of matter known in the art ofchemistry as Z-benzyl-1,3-diaza-2,3-cycloalkenes and to theirpreparation.

The invention in its composition aspect resides in the compounds havingthe Formula I where R is lower-alkyl, R is hydrogen, lower-alkyl orlower-alkenyl, R is hydrogen or lower-alkyl, and Y is alkylene of 2-8carbon atoms in which 2-4 carbon atoms intervene between the valencelinkages, said compounds being, respectively, Z-imidazolines,1,4,5,6-tetrahydropyrimidines and 4,5,6,7-tetrahydro-lH-1,3-diazepines.The compounds of this composition aspect of the invention, when testedaccording to standard pharmacological evaluation procedures in animals,have been found to possess the inherent applied use characteristics ofhaving pharmacological properties, e.g., anti-inflammatory andhypoglycemic activities. Further, said tetrahydropyrimidines andtetrahydro-IH-1,3-diazepines of the invention have been found to havediuretic activity, as determined by standard pharmacological procedures.

The above Z-imidazolines and 1,4,S,6-tetrahydropyrimidines of Formula Iare disclosed and claimed in copending application Ser. No. 26,787,filed Apr. 8, 1970, a continuation-in-part of the instant application.

The substitution of simple moieties on the benzene ring of phenyl in thecompounds of the invention does not adversely affect the pharmacologicalactivity of the compounds. Illustrative but not limitative examples ofsuch simple moieties are lower-alkyl, lower-alkoxy, halo, trihalomethyl,loWer-alkylmercapto, lower-alkylsulfonyl, di- (lower-alkyl)amino, amino,hydroxy, nitro and benzyloxy. Such substituent moieties can be in anyavailable position of the benzene ring and where more than one,preferably no more than three, can be in any position relative to oneanother. Also, phenyl in the compounds of the invention can be replacedby other simple ring moieties without affecting the pharmacologicalactivity of the compounds. Illustrative but not limitative examples ofsuch other simple ring moieties are naphthyl, indanyl, biphenylyl,cyclohexenyl and cyclohexyl.

The terms loWer-alkyl and loweralkoxy, as used herein, respectively,mean alkyl and alkoxy radicals having from one to six carbon atoms whichcan be arranged as straight or branched chains, among which are, forpurposes of illustration but without limiting the generality of theforegoing, methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl andn-hexyl for lower-alkyl; and, by methoxy, ethoxy, n-propoxy, isopropoxy,isobutoxy, n-amoxy and nhexoxy for lower-alkoxy.

The term lower-alkenyl, as used herein, means alkenyl radicals havingfrom three to six carbon atoms, among which are, for purposes ofillustration but without limiting the generality of the foregoing,Z-propenyl (allyl), 2- butenyl, 2-methyl-2-propenyl, 2-hexenyl, and thelike.

The invention sought to be patented, in its process aspect, is describedas residing in the process for the preparation of the composition aspectof the invention, that is, the compound of Formula I, which comprisesheating a 2-(lower-alkoxy)-2-phenylalkanenitrile of Formula II (I) Rphenyl-(|3 CN R II with an alkanediamine of the Formula III H NYNHR IIIin the presence of a catalytic amount of carbon disulfide or hydrogensulfide, where R, R, R and Y have the meanings given hereinabove forFormula I.

In the above-described process where the alkane-diamine of Formula IIIhas 2, 3 or 4 carbon atoms intervening between the valence linkages ofalkylene (Y), i.e., between the two amino nitrogen atoms, the resultingproducts are, respectively, 2-[u-(lower-alkoxy)benzyl]-2-imidazolines,2- [u-(lower-alkoxy)benzyl] -1,4,5,6-tetrahydropyrimidines or2-[a-(lower-alkoxy)benzyl]-4,5,6,7-tetrahydro-1H-l,3-diazepines.

The alkanediamine of Formula III used in the above condensation can havea hydroxy or lower-alkoxy substituent on a carbon atom not bearing anamino group, and the use of such diamines gives rise to2-[a-(lower-alkoxy) benzyl1-1,4,5,6-tetrahydropyrimidines and2-[a-(lower-alkoxy)benzyl]-4,5,6,7-tetrahydro-1H 1,3-diazepines havinghydroxy or lower-alkoxy in the Y portion of Formula I.

Examination of the final products of Formula I, upon infrared andnuclear magnetic resonance spectographic analyses, reveals dataconfirming the molecular structures assigned to these compounds. Thesedata, taken together with the nature of the starting material, mode ofsynthesis and results of elementary analyses, positively confirm thestructures of the final products.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofmedicinal chemistr to make and use the same, as follows:

PREPARATION OF INTERMEDIATES The intermediate 2-(lower-alkoxy) 2phenylalkanenitriles (Formula II), examples of which are known, e.g.,2-ethoxy-Z-phenylethanenitrile (or a-ethoxyphenylacetonitrile),2-methoxy-2-phenylethanenitrile and 2-ethoxy-2-(4-methoxyphenyl)ethanenitrile, are prepared by generally known methods.For example, one method found convenient utilized three steps by firstreacting the corresponding generally known benzaldehydes with atri-(lower-alkyl) orthoformate of the formula HC(OR) to form thecorresponding aldehyde di-(lower-alkyl) acetal of the formulaphenyl-(CH(OR) which is then reacted with a lower-alkanoyl halide, e.g.,acetyl chloride, to form the corresponding a-halobenzyl lower-alkylether of the formula phenyl-CHC1(OR) which in turn is reacted with analkali cyanide, e.g., sodium cyanide, to yield thedlower-alkoxy)phenylacetonitrile of the formula phenyl- CH(OR)CN, thatis, the compound of Formula II where R is hydrogen. Reaction of thiscompound with a loweralkylating agent, e.g., a lower-alkyl halide, inthe presence of a strong base, e.g., potassium tertiary-butoxide,sodamide, etc., yields the compounds of Formula II where R' islower-alkyl.

The compounds of Formula II where R is hydrogen also can be prepared bythe generally known method of heating the correspondinga-(lower-alkoxy)phenylacetamide of the formula phenyl-CH(OR)CONH with adehydrating agent effective to convert carboxamides to nitriles, e.g.,thionyl chloride. Said a-(lower-alkoxy)phenylacetamides are preparedfrom the corresponding generally known oc-(lower-alkoxy)phenylaceticacids by the generally known procedures of converting said acids totheir acid chlorides by reaction with thionyl chloride and reacting saidacid chlorides with ammonia to form said carboxamides.

PREPARATION OF FINAL PRODUCTS The final products, as illustrated byFormula I, are prepared by heating a2-(lower-alkoxy)-2-phenylalkanenitrile of Formula II with analkanediamine of Formula III in the ,presence of a catalytic amount ofcarbon disulfide or hydrogen sulfide. This reaction is carried out byheating the reactants in the presence of the sulfide catalyst,preferably with stirring under an inert atmosphere, e.g., nitrogen, atabout 70 to 200 C., preferably between about 90 and 150 C.

Alternatively, and less preferably, the final products can be preparedby heating the corresponding 2-(loweralkoxy)-2phenylalkanoic acid orlower-alkyl ester thereof, preferably methyl or ethyl ester, with saidalkanediamine, e.g., 1,2-ethanediamine, 1,3-propanediamine or 1,4-butanediamine, generally at higher temperatures than used with thenitriles, i.e., about l40200 0, preferably about 140-160" C.

The best mode contemplated for carrying out the invention will now beset forth as follows:

(A) ALDEHYDE -DI-(LOWER-ALKYL) ACETALS (1) Benzaldehyde diethyl acetal.Amixture containing 160 g. of benzaldehyde, 161 g. of triethylorthoformate, 138 g. of ethanol and 2 g. of finely powdered ammoniumchloride was refluxed on a steam bath for fifteen minutes; the excessreactants were then distilled off at about 85 C.; and the remainingmaterial was distilled in vacuo. After a fore-run of ethyl orthoformate(B.P., C. at 10 mm.), 160 g. of benzaldehyde diethyl acetal wascollected at 97-99 C./ 10 mm.

(2) l-naphthaldehyde dimethyl acetal.-To 134 g. of l-naphthaldehyde in aone liter round bottom flask was added successively 120 g. of trimethylorthoformate, 120 ml. of methanol and two drops of concentratedhydrochloric acid. After the initial vigorous reaction had subsided, thesolution was refluxed for thirty minutes and then the excess reagentswere removed by distilling under reduced pressure. The residue wasdistilled in vacuo to yield 160 g. of 1-naphthaldehyde dimethyl acetal,B.P. 94 C. at 0.12 mm.

(3) 2,6-dichlorobenzaldehyde diethyl acetal.l43 g., was prepared bystirring a mixture containing 100 g. of 2,6-dichlorobenzaldehyde, 90 g.of triethyl orthoformate, 90 ml. of ethanol and 0.5 ml. of concentratedhydrochloric acid for forty-five minutes at room temperature (25-30 C.),for forty-five minutes on a steam bath and one hour at room temperature,followed by removal of the excess reactants by distilling in vacuo at C.using a water pump. The product was used in the next step without anyfurther purification.

(4) 2-chlorobenzaldehyde diethyl acetal.-835 g., as a clear pale yellowoil, was prepared as in Example A-3 using 500 g. of2-chlorobenzaldehyde, 634 g. of triethyl orthoformate, 625 ml. ofethanol and 1 ml. of concentrated hydrochloric acid.

(5) 4-chlorobenzaldehyde diethyl acetal.168.5 g., B.P. 126-129 C. at 15mm., was prepared by refluxing for thirty minutes a mixture containing140.6 g. of 4- chlorobenzaldehyde, 178 g. of triethyl orthoformate, 175ml. of ethanol and 1 ml. of concentrated hydrochloric acid; distillingoff in vacuo (at C. using a water pump) the solvent and excessreactants; and, distilling the residue under high vacuum.

(6) Indane-S-carboxaldehyde diethyl acetal.281 g., B.P. 139-140 C. at 9mm., was prepared as in Example A-5 using 200 g. ofindane-S-carboxaldehyde, 244 g. of triethyl orthoformate, 200 ml. ofabsolute ethanol, 1 ml. of concentrated hydrochloric acid and a refluxperiod of one hour.

(7) l-naphthaldehyde diethyl acetal.-l97 g., B.P. -101 C. at 0.16-0.17mm., was prepared as in Example A-2 using 156.2 g. of l-naphthaldehyde,196 g. of triethyl orthoformate, ml. of ethanol and two drops ofconcentrated hydrochloric acid.

(8) 3-fluorobenzaldehyde diethyl acetal.l40.8 g. B.P. 91-95 C. at 1 mm.,was prepared as in Example A-5 using 124 g. of 3-fluorobenzaldehyde, 163g. of ethyl orthoformate, ml. of absolute ethanol, three drops ofconcentrated hydrochloric acid and a reflux period of thirty minutesafter the 3-fluorobenzaldehyde had been added in three equal portionswith stirring to the other reactants.

(9) 4-isopropylbenzaldehyde diethyl acetal.-198.1 g., was prepared as inExample A-3 using 148 g. of 4-isopropylbenzaldehyde, g. of triethylorthoformate, 150 ml. of absolute ethanol, 2 ml. of concentratedhydrochloric acid and a reflux period of one hour after mixing thereactants.

(l0) 4-methoxybenzaldehyde diethyl acetal.422 g., was prepared as inExample A-9 using 242 ml. of 4- methoxybenzaldehyde (anisic aldehyde),326 g. of triethyl orthoformate, 250 ml. of absolute ethanol and sixdrops of concentrated hydrochloric acid.

(11) Benzaldehyde dimethyl acetal-146.2 g., B.P. 98-103 C. at 31-37 mm.,was prepared as in Example A-5 using 106.1 g. of benzaldehyde, 127.5 g.of triethyl orthoformate, 96.1 g. of anhydrous methanol and one drop ofconcentrated hydrochloric acid.

(12) 4-methylbenzaldehyde diethyl acetal.-387 g., was prepared as inExample A-3 using 240 g. of 4-methylbenzaldehyde, 296 g. of triethylorthoformate, 350 ml. of absolute ethanol and six drops of concentratedhydrochloric acid, allowing the reactants to stand for ten minutes aftermixing before heating on a steam bath for about thirty minutes.

(13) 2-naphthaldehyde diethyl acetal.102.4 g., B.P. 105-108 C. at 0.02mm., was prepared as in Example A-S using 90 g. of Z-naphthaldehyde,121.5 g. of triethyl orthoformate, 90 ml. of absolute ethanol and twodrops of concentrated hydrochloric acid, stirring the reactants forabout thirty minutes and then refluxing for forty-five minutes.

(14) 3,4-dich1orobenzaldehyde diethyl acetal.-A mixture containing 175g. of 3,4-dichlorobenzaldehyde, 178 g. of triethyl orthoformate, 100 ml.of absolute ethanol and 100 ml. of ethanolic hydrogen chloride solutionwas stirred under reflux for thirty minutes. The reaction mixture wasthen cooled and neutralized with sodium ethoxide solution prepared from2.3 g. of sodium and 100 ml. of absolute ethanol. The solvent wasdistilled off in vacuo; the residue was cooled in an ice bath anddiluted with 300 ml. of benzene; and, the resulting mixture was pouredinto 200 ml. of cooled aqueous sodium hydroxide solution. The benzenelayer was separated, washed with 200 ml. of water, dried over anhydroussodium sulfate, filtered through anhydrous sodium sulfate and heated ona steam bath in vacuo to remove any solvent. The residue was thendistilled in vacuo to yield a 201.7 g. fraction of3,4-dichlorobenzaldehyde diethyl acetal, B.P. 73-88 C. at 0185-0310 mm.

(15) Benzaldehyde di-n-propyl acetal-A mixture containing 210 g. ofbenzaldehyde dimethyl acetal, 1 liter of n-propanol and 1 drop ofconcentrated hydrochloric acid was fractionally distilled through a 9column packed with glass helices. After removing the methanol atatmospheric pressure, then removing the excess n-propanol using a rotaryevaporator, the product, benzaldehyde din-propyl acetal B.P. 242245 C.,was distilled at atmospheric pressure.

(16) Benzaldehyde di-n-butyl acetal.-247.3 g., B.P. 112-115 C. at 1.7mm., was prepared using the procedure of Stewart et a1. [JACS 77, 1098(1955)] using 202 ml. of benzaldehyde, 600 ml. of n-butanol and twodrops of concentrated hydrochloric acid.

(17) Z-methoxybenzaldehyde diethyl acetal-405 g., was prepared as inExample A-3 using 65 g. of 2-methoxybenzaldehyde, 90 g. of triethylorthoformate, 200 ml. of absolute ethanol and 1 ml. of concentratedhydrochloric acid.

(18) 4-benzyloxybenzaldehyde diethyl acetal.To a suspension containing100 g. of 4-benzyloxybenzaldehyde, 90 g. of triethyl orthoformate and250 ml. of absolute ethanol was added 1 ml. of concentrated hydrochloricacid. After allowing the reaction mixture to stand for one hour at about-30 C., g. of solid potassium carbonate was added and the resultingmixture was stirred for five minutes and filtered. The filtrate wasevaporated in vacuo to yield 135 g. of 4-benzyloxybenzaldehyde diethylacetal.

(19) 3-cyclohexenealdehyde diethyl acetal.To a stirred solutioncontaining 128.5 g. of 3-cyclohexenealdehyde(1,2,3,6-tetrahydrobenza1dehyde) and 250 ml. of absolute ethanol wasadded successively a few mg. of ptoluenesulfonic acid and 220 ml. oftriethyl orthoformate, the latter at such a rate to maintain thereaction temperature at about 38 C. (aided by cooling in an ice bath).

The reaction mixture was stirred at room temperature for seventeenhours, warmed on a steam bath to reflux (reaction temperature 78 C.) fortwo hours, cooled and distilled in vacuo to remove the ethanol andexcess triethyl orthoformate. The remaining viscous yellow oily residuewas dissolved in 500 ml. of ether and the solution ex tractedsuccessively with 10% aqueous sodium hydroxide solution three times andthen with water. The ether solution was then dried over anhydrousmagnesium sulfate and the ether removed by distilling in vacuo, therebyyielding 208 g. of 3-cyclohexenealdehyde diethyl acetal.

(20) 3-fluoro-4-methoxybenzaldehyde diethyl acetal. 192 g., was preparedas in Example A-3 using 122 g. of 3- fluoro-4-methoxybenzaldehyde, 170g. of triethyl orthoformate, 200 ml. of absolute ethanol and three dropsof concentrated hydrochloric acid.

(B) ALPHA-HALOBENZYL LOWER- ALKYL ETHERS (1) a-Chlorobenzyl ethylether.tA mixture containmg 157 g. of benzaldehyde diethyl acetal, 180 g.of acetyl chloride and 1.5 ml. of thionyl chloride was stirred at roomtemperature (25-30 C.) overnight (about fifteen hours). The volatileliquids (excess acetyl chloride and ethyl acetate were removed underreduced pressure and the residue was fractionated in vacuo to yield139.5 g. of u-ChlOIObGIlZYl ethyl ether, B.P. 58-60 C. at 0.2 mm.

(2) a,3,4-trichlorobenzyl ethyl ether.218.2 g., was prepared as inExample B-1 using 229.5 g. of 3,4-dichlorobenzaldehyde diethyl acetal,393 ml. of acetyl chloride and 3.5 ml. of thionyl chloride. The ether,not distilled, was obtained after removal of volatile liquids from thereaction mixture and heating the residue at C. and 0.07 mm.

(3) l-naphthylchloromethyl methyl ether.-A mixture containing 160 g. ofl-naphthaldehyde dimethyl acetal and 280 ml. of acetyl chloride in aflask equipped with a reflux condenser and a calcium chloride tube wasallowed to stand at room temperature overnight. The excess acetylchloride and the methyl acetate formed during the reaction were removedin vacuo at 30 C. to yield 160 g. of l-naphthylchloromethyl methylether.

(4) ot-Chlorobenzyl methyl ether.-131.7 g., was prepared as in ExampleB-3 using 146.2 g. of benzaldehyde dimethyl acetal and 408 ml. of acetylchloride.

(5) a,4-dichlorobenzyl ethyl ether.-To a stirred mixture containing 280ml. of acetyl chloride and 2 ml. of thionyl chloride was added dropwiseat about 30 C. 168.5 g. of 4-chlorobenzaldehyde diethyl acetal over aperiod of about forty minutes. The reaction mixture was then allowed tostand overnight at room temperature. The solvent was removed in vacuo ata temperature below 40 C. and then the residue was heated in vacuo at 50C. for about thirty minutes to yield 152 g. of oz,4-diChlOI0- benzylethyl ether.

(6) u,2,6-trichlorobenzyl ethyl ether.-139 g., was prepared as inExample B-S using 143 g. of 2,6-dichlorobenzaldehyde diethyl acetal, 200ml. of acetyl chloride and 100 ml. of thionyl chloride. A 15 g. sampledistilled at 82-83 C. at 0.06 mm.

(1) u,2-dich1orobenzyl ethyl ether.-826 g., was prepared as in ExampleB-S using 835 g. of 2-ch1orobenzaldehyde diethyl acetal, 1260 ml. ofacetyl chloride and 2 ml. of thionyl chloride.

(8) a-Chloro-3-fiuorobenzyl ethyl ether.-To 330 ml. of acetyl chloridecontaining 1 ml. of ethanol was added dropwise with stirring over aperiod of about one hour 184 g. of 3-fiuorobenzaldehyde diethyl acetal,keeping the temperature between about 25-30 C. by intermittent coolingwith and ice bath. The solution was allowed to stand overnight at roomtemperature and then heated in vacuo below 40 C. to remove the excessacetyl chloride and ethyl acetate. The residue was then heated in vacuoat 50 C. for an hour to yield g. of u-chloro-3-fiuorobenzyl ethyl ether.

(9) a-Chloro-4-methoxybenzyl ethyl ether.401 g., was prepared as inExample B-8 using 422 g. of 4-methoxybenzaldehyde diethyl acetal, 357ml. of acetyl chlo ride and 1 ml. of ethanol.

(10) a-Chloro-Z-naphthylmethyl ethyl ether.-10l g., was prepared as inExample B8 using 106 g. of 2- naphthaldehyde diethyl acetal and 82 ml.of acetyl chloride.

(11) ot-chloro-l-naphthylmethyl ether ether.l87 g. was prepared as inExample B-8 but using 2 ml. of thionyl chloride together with 350 ml. ofacetyl chloride and 196.5 g. of l-naphthaldehyde diethyl acetal.

(12) a-Chloro-4-isopropylbenzyl ethyl ether.-189 g. was prepared as inExample B8 using 198 g. of 4-isopropylbenzaldehyde diethyl acetal, 160ml. of acetyl chloride and 1 ml. of ethanol.

(13) a-Chlorobenzyl n-propyl ether.92.4 g., was prepared as in ExampleB-8 using 104 g. of benzaldehyde di-n-propyl acetal and 178 ml. ofacetyl chloride.

(14) a-Chlorobenzyl n-butyl ether.198 g., was prepared as in Example B-8using 236 g. of benzaldehyde di-n-butyl acetal, 178 ml. of acetylchloride and a few drops of ethanol.

(15) et-Chloro-4-methylbenzyl ethyl ether.--185 g., was prepared as inExample B-8 using 194 g. of 4- methylbenzaldehyde diethyl acetal, 284ml. of acetyl chloride and 3 ml. of thionyl chloride.

(16) tx-Chloro-5-indanylmethyl ethyl ether.104 g., was prepared as inExample B-8 using 281 g. of indane-S- carboxaldehyde diethyl acetal and400 ml. of acetyl chloride.

(17) a-Chloro-2-methoxybenzyl ethyl ether.96 g. was prepared as inExample B-5 using 105 g. of 2-methoxybenzaldehyde diethyl acetal, 160ml. of acetyl chloride and 1 ml. of thionyl chloride.

(18) 4-benzyloxy-a-chlorobenzyl ethyl ether was prepared as in ExampleB-8 using 135 g. of 4-benzyloxybenzaldehyde diethyl acetal, 106 ml. ofacetyl chloride and 1 ml. of thionyl chloride.

(19) a-Chloro-l,2,3,6-tetrahydrobenzyl ethyl ether. 156 g., was preparedas in Examplre B-8 using 198 g. of 1,2,3,6-tetrahydrobenzaldehydediethyl acetal, 700 ml. of acetyl chloride and 1 ml. of thionylchloride.

(20) a-Chloro-3-fiuoro-4-methoxybenzyl ether ether. 176 g., was preparedas in Example B-8 using 192 g. of 3-fluoro-4-methoxybenzyldehyde diethylacetal, 500 g. of acetyl chloride and 1 ml. of thionyl chloride.

(C) ALPHA (LOWER-ALKOXY)PHENYLACETO- NITRILES FROM ALPHAHALOBENZYLLOWER- ALKYL ETHERS (l) ot-Ethoxphenylacetonitrile.To a suspensioncontaining 37.8 g. of sodium cyanide in 400 ml. of dimethylformamide wasadded dropwise with stirring over a period of about forty-five minutes,keeping the mixture below C., a solution containing 105 g. ofa-chlorobenzyl ethyl ether in 100 ml. of dimethylformamide. The mixturewas stirred for an additional thirty minutes; the solids were filteredoff; the solvent was distilled off under reduced pressure; and, theresidue was fractionally distilled to yield 66 g. ofa-ethoxyphenylacetonitrile, B.P. 114116 C. at 10 mm.

(2) oz Ethoxy-2,6-dichlorophenylacetonitrile.63 g., B.P. 97 C. at 0.05mrn., was prepared as in Example C-l using 36 g. of sodium cyanidesuspended in 250 ml. of dimethylformamide and 124 g. ofa,2,6-dichlorobenzyl ethyl ether and 40 ml. of dimethylformamide. Beforedistillation, infusorial earth Was added to the reaction mixture; themixture was filtered; and the filter cake was washed with benzene; and,the filtrate was evaporated on a rotary evaporator, removing the last ofthe dimethylformamide through a fractionating column using a water pump.

(3) a Ethoxy 2 chlorophenylacetonitrile.-To a stirred suspensioncontaining 204 g. of sodium cyanide in 1500 ml. of dimethylformamide wasadded over a period of about two hours, keeping the reaction mixture atabout 2025 C., 676 g. of u,2-dichlorobenzyl ethyl ether and theresulting mixture was stirred for an additional hour. To the reactionmixture was added 800 ml. (dry volume) of infusorial earth and themixture was filtered through infusorial earth. The filter pad was washedWith benzene. The combined filtrate and washings were evaporated invacuo at about 20-40 mm. and C. The residue was taken up With 1500 ml.of 1:1 benzene-ether and the resulting solution treated with 2 liters ofice water containing 200 ml. of 10% aqueous sodium hydroxide solution.The aqueous layer was drained off and discarded. The organic layer waswashed with two 500 ml. portions of water and with 250 ml. portions ofbrine, and then dried overnight over anhydrous sodium sulfate. Thesolvent was distilled off in vacuo and the residue fractionallydistilled to yield 379.2 g. of a-ethoxy-2-chlorophenylacetonitrile, B.P.9397 C. at 1.4 mm.

(4) tx-Ethoxy-4-chlorophenylacetonitrile.88.5 g., B.P. 103-105 C. at 1.3mrn., was prepared as in Example C2 using 49 g. of sodium cyanide indimethylformamide and 152 g. of a,4-dichlorobenzyl ethyl ether.

(5) a-Methoxy-l-naphthylacetonitrile, 68 g., B.P. 124- 126 C. at0.27-0.28 mrn., was prepared as in Example C3 using 49 g. of sodiumcyanide in 500 ml. of dimethylformamide and 160 g. ofa-chloro-l-naphthylmethyl methyl ether in 250 ml. of dimethylformamide.

(6) a-Ethoxy-3,4 dichlorophenylacetonitrile.24.5 g. at 78-90 C. and0015-0025 mm. and 14.9 g. at 108 C. and 0.05 mrn., was prepared as inExample Cl using 50.5 g. of sodium cyanide suspended in 545 ml. ofdimethylformamide and 198.2 g. of a,3,4,-trichlorobenzyl ethyl ether inml. of dimethylformamide.

(7) u-Methoxyphenylacetonitrile.-55.5 g., B.P. 59- 68.5 C. at 0.03-0.14mrn., was prepared as in Example C1 using 51.5 g. of sodium cyanide in553 ml. of dimethylformamide and 131. 7 g. of a-chlorobenzyl methylether in 141 ml. of dimethylformamide.

(8) a-n-propoxyphenylacetonitrile.57.3 g., B.P. l00 103 C. at 2 mrn.,was prepared as in Example C-3 but using only ether (no benzene) toextract the product and using 30.6 g. of sodium cyanide in 200 ml. ofdimethylformamide and 92.4 g. of a-chlorobenzyl n-propyl ether.

(9) a n butoxyphenylacetonitrile.122.9 g., B.P. 105.5l07.5 C. at 1.5mrn., was prepared as in Example C-8 using 61.2 g. of sodium cyanide in500 ml. of dimethylformamide and 198 g. of n-butyl a-chlorobenzyl ether.

(10) OL-EflflOXY 3 fluorophenylacetonitrile.54.6 g., B.P. 75-78 C. at0.17 mrn., was prepared as in Example C-8 using 57 g. of sodium cyanidein 600 ml. of dimethylformamide and g. of a-chloro-3-fluorobenzyl ethylether.

(11) a-Ethoxy-4-methoxyphenylacetonitrile.299.5 g., B.P. 118-125 C. at1.5 mrn., was prepared as in Example C-8 using 122.5 g. of sodiumcyanide in 900 ml. of dimethylformamide and 401 g. ofa-chloro-4-methoxybenzyl ethyl ether.

(12) a-Ethoxy 2 naphthylacetonitrile.40.44 g., B.P. 119-121 C. at 0.09mrn., was prepared as in Example C-8 using 28.2 g. of sodium cyanide in350 ml. of dimethylformamide and 101 g. of ot-chloro-2-naphthylmethylethyl ether. The product solidified on standing and was found to melt at5254 C.

(13) OL-EthOXy 4 isopropylphenylacetonitrile.109.6 g., B.P. 86-92 C. at0.10 mrn., was prepared as in Example C-8 using 55 g. of sodium cyanidein 400 ml. of dimethylformamide and 189 g. of a-chloro-4-isopropylben-Zyl ethyl ether.

(14) a-Ethoxy 1 naphthylacetonitrile.97.3 g., B.P. 135-139 C. at0.09-0.12 mrn., was prepared as in Example C-S using 50 g. of sodiumcyanide in 850 ml. of di methylformamide and 182 g. ofa-chloro-l-naphthylmethyl ethyl ether.

(15) a Ethoxy 4 methylphenylacetonitrile.-89 g., 133-135 C. at 9 mm.,was prepared as in Example C-8 using 61 g. of sodium cyanide in 300 ml.of dimethylformamide and 172 g. of ot-chloro-4-methylbenzyl ethyl ether.

(16) u-Ethoxy indanylacetonitrile.-104 g., B.P. 122-126 C. at 1.4 mm.,was prepared as in Example C-8 using 78.5 g. of sodium cyanide in 650ml. of dimethylformamide and 269.8 g. of a-chloro-5-indanylmethyl ethylether. Before fractionating, the reaction mixture was diluted with 1300ml. of water, the mixture extracted three times with benzene, theextract washed with water, dried over anhydrous potassium carbonate andevaporated in vacuo to remove the benzene.

(17 a Ethoxy 2 methoxyphenylacetonitrile.B.P. Ill-113 C. at 1.3 mm., wasprepared as in Example C-8 using 30 g. of sodium cyanide in 250 ml. ofdimethylformamide and 96 g. of u-chloro-2-methoxybenzyl ethyl ether.

(18) 4-benzyloxy a ethoxyphenylacetonitrile.To a stirred mixturecontaining 30 g. of sodium cyanide in 250 ml. of dimethylformamide wasadded dropwise over a period of forty-five minutes4-benzyloxy-a-chlorobenzyl ethyl ether prepared from 135 g. of4-benzyloxybenzaldehyde diethyl acetal (Example B-18), maintaining thereaction temperature at about 20-25 C. by slight external cooling. Thereaction mixture was stirred for an additional three hours, infusorialearth was added and the mixture filtered through infusorial earth. Thefilter cake was washed successively with dimethylformamide and benzene.The combined filtrate and washings were evaporated to a low volume andwas taken up in a mixture of henzene, ether and water. The layers wereseparated and the organic layer was washed three times with water andthen stirred vigorously for one hour with 100 ml. of 1 N hydrochloricacid. The layers were separated and the organic layer was washed withaqueous sodium bicarbonate solution, dried over anhydrous potassiumcarbonate while treating with decolorizing charcoal, the mixturefiltered and the filtrate evaporated in vacuo to remove the ether andbenzene. The residue was distilled under reduced pressure to yield 53.7g. of 4-benzyloxy-e-ethoxyphenylacetonitrile, B.P. 155-158 C. at0.03-0.04 mm.

(19) u ethoxy 3 cyclohexenylacetonitrile.13.6 g. B.P. 97-99 'C., at 8mm., was prepared as in Example C-3 using 23 g. of sodium cyanide, 400ml. of dimethylformamide, 80 g. of e chloro 1,2,3,6tetrahydrobenzaldehyde ethyl ether and ether instead of benzeneether inthe work-up.

(20) 3 chloro a ethoxyphenylacetonitrile.-B.P. 89-91" C. at 0.14 mm,67.11 g., was prepared as in Example C-8 using 53.9 g. of sodiumcyanide, 300 ml. of dimethylformamide and 146 g. of a,3-dichlorobenzylethyl ether.

(21) a ethoxy 3 fiuoro 4 methoxyphenylacetonitrile.B.P. 125-129 C. at1.4 mm, 81.3 g., was prepared as in Example C-8 using 49 g. of sodiumcyanide, 500 ml. of dimethylformamide and a chloro 3 fluoro-4-methoxybenzyl ethyl ether.

Following the procedure described in Example C, e.g., C-1, C-3 or C-8using corresponding molar equivalents of the appropriate ot-halobenzyllower-alkyl ether, the following a (lower alkoxy)phenylacetonitriles areprepared: 3 fluoro a n propoxyphenylacetonitrile using on chloro 3fluorobenzyl n-propyl ether; 2,4-dibromoa ethoxyphenylacetonitrile using2,4 dibromo a chlorobenzyl ethyl ether; a,3,4triethoxyphenylacetonitrile using a chloro 3,4 diethoxybenzyl ethylether; ozethoxy 3 diethylaminophenylacetonitrile using u-chlor0 3diethylaminobenzyl ethyl ether; or n butoxy-4-methylmercaptophenylacetonitrile using a chloro 4-methylmercaptobenzyl n-butyl ether; orethoxy-4-rnethylsulfonylphenylacetonitrile using a chloro 4methylsulfonyl benzyl ethyl ether; or ethoxy 4 biphenylylacetonitrileusing on chloro 4 biphenylylmethyl ethyl ether; 4 chloro a nhexoxyphenylacetonitrile using 11,4 dichlorobenzyl n-hexyl ether; orethoxy 3 fluoro- 4 methoxyphenylacetonitrile using a chloro 3 fluoro-4-methoxybenzyl ethyl ether; 4 chloro or ethoxy-2-nitrophenylacetonitrile using a,4 dichloro 2 nitrobenzyl ethyl ether.The foregoing intermediate or halobenzyl lower-alkyl ethers are preparedin two steps starting with the appropriate corresponding aldehyde andfollowing the procedures described above in Example A, e.g., A-l, A-3,A-l5 or A-l6, and Example B, e.g., B-l, B-2, 13-5 or B-8, first to formthe corresponding aldehyde di (lower alkyl) acetals and then thecorresponding a-halobenzyl lower-alkyl ethers.

(D) ALPHA- (LOWER-ALKOXY) PHENYLACETIC ACIDS, ESTERS AND AMIDES (1)a-methoxyphenylacetamide.-A solution of 30 g. of ethylot-chlorophenylacetate in ml. of 1.6 M methanolic sodium methylate wasrefluxed for three hours, the solvent stripped ofl" and the residuepartitioned between ether and cold dilute hydrochloric acid.Distillation of dried ether solution yielded 16 g. of ethylamethoxyphenylacetate, B.P. -132 C. at 19 mm. This ester was dissolvedin 300 ml. of methanol which previously had been saturated with ammoniaand the solution was allowed to remain at room temperature for threedays. The solvent was removed and the residue recrystallized frombenzene to yield 7.5 g. of a-methoxyphenylacetamide, M.P. Ill-112 C.

(2) u-methoxyphenylacetamide.To a stirred solution containing 53.5 g. ofbenzaldehyde, 89.5 g. of chloroform and 100 ml. of methanol, maintainedat 40-45 C, there was added dropwise a solution of g. of potassiumhydroxide in 400 ml. of methanol. After standing at room temperature forfourteen hours, the reaction mixture was stripped of solvent and theresidual material was dissolved in water. The aqueous solution wasfiltered through decolorizing charcoal, and the filtrate was acidifiedand extracted with ether. Distillation of dried ether solution yielded44 g. of a-methoxyphenylacetic acid, B.P. 130- 134 C. at 0.7 mm. andM.P. 68-70 C. after recrystallizing from benzenepetroleum ether. Thirtygrams of a-methoxyphenylacetic acid was added to a mixture of 30 ml. ofthionyl chloride and 100 ml. of chloroform, and the mixture was refluxedfor eight hours. The volatile liquids were removed by distilling invacuo and the residue was dissolved in a small amount of acetone. Theacetone solution was added slowly to ammonium hydroxide containing ice.The reaction mixture was distilled in vacuo and the remaining dryresidue was recrystallized from aqueous isopropyl alcohol usingdecolorizing charcoal to yield 15.8 g. of a-methoxyphenylacetamide, M.P.109-111 C.

(3) a methoxy a 3 trifluoromethylphenylacetamide.-A solution of 10.4 g.of 3-trifluoromethylbenzaldehyde and 17.2 g. of bromoform in 50 ml. ofmethanol was stirred at 0-5 C. while a solution of 18 g. of potassiumhydroxide in 100 ml. of methanol was added over a period of 90 minutes.The mixture was allowed to remain overnight in a melting ice bath andthen most of the alcohol was removed by ether extraction and thesolution acidified. The precipitated oily material was extracted anddistilled to yield 8 g. of a methoxy 3 trifluoromethylphenylacetic acid,B.P. 120-122 C. at 0.4 mm. This acid was converted into its acidchloride by refluxing a solution of 12 g. of the acid in 25 ml. ofthionyl chloride for two hours and removing the excess thionyl chlorideby vacuum-distillation. The acid chloride was added slowly to ammoniumhydroxide containing ice and the semi-solid amide was collected andrecrystallized twice from benzenepetroleum ether to yield 4.5 g. ofamethoxy 3 trifluoromethylphenylacetamide, MP. 96- 97 C.

(4) a n butoxyphenylacetamide.-To a stirred solution of 32.4 g. ofbenzaldehyde, 81 g. of bromoform and 100 ml. of n-butanol kept at about5-10 C. was added dropwise a solution prepared by reacting 34.5 g. ofsodium with 700 ml. of n-butanol. After remaining overnight, the mixturewas distilled to dryness and the residue taken up in water. The aqueoussolution was clarified by ether extract, acidified and the precipitatedoily acid was extracted with ether and fractionated to yield 14.1 g. ofa-n-butoxyphenylacetic acid, B.P. 130 132 C. at 0.4 mm. This acid (14g.) was combined with 25 ml. thionyl chloride and 50 ml. of benzene andrefluxed for two hours. The solvent was removed and the residue wasadded to iced ammonium hydroxide to yield 7 g. ofa-n-butoxyphenylacetamide, M.P. 84-85 C., after recrystallization fromn-heptane.

(5) 4-chloro a -methoxyphenylacetamide, M.P. 133- 134 C., was preparedin 37% yield as in Example D3 using corresponding molar equivalentquantities of 4-chlorobenzaldehyde, bromoform and methanol to form4-chloro-a-methoxyphenylacetic acid, B.P. 148149 C. at 0.5 mm. and M.P.82-84 C. and converting the acid to its acid chloride using thionylchloride and reacting the acid with ammonia to yield the amide.

(6) a-Ethoxyphenylacetamide.B.P. 140-144 C. at 0.4 mm. and M.P. 7274 C.after recrystallization from n-heptane, was obtained as in Example D-2first using corresponding molar equivalent quantities of benzaldehyde,chloroform and ethanol in the presence of potassium hydroxide to give a37% yield of u-ethoxyphenylacetic acid, B.P. 137l79 C. at 0.7 mm.; andthen successively converting the acid to its acid chloride with thionylchloride and then to its amide with ammonia.

(7) a-Methoxy-4-biphenylylacetic acid.-To a stirred suspension of 25 g.of 4-biphenylcarboxaldehyde, 37.8 g. of bromoform and 150 ml. ofmethanol stirred at 5 C. was added dropwise a solution of 48 g. of 85%potassium hydroxide in 230 ml. of methanol. About one-half of thepotassium hydroxide-methanol solution was added over a thirty minuteperiod and the remainder was added more rapidly over a fifteen minuteperiod. The reaction mixture was stirred in a melting ice bath for abouttwenty hours and evaporated in vacuo to remove the methanol and water.The residue was taken up with a mixture of ethyl acetate and water. Theaqueous layer was separated and acidified. The acidic solution wasextracted with chloroform and the remaining acidic solution evaporatedin vacuo. The remaining solid residue was crystallized first frombenzene and then from isopropyl alcohol to yield 13.6 g. ofu-methoxy-4-biphenylylacetic acid, M.P. 130.5-133" C.

(E) ALPHA (LOWER ALKOXY) PHENYLACETO- NITRILES FROM ALPHA (LOWERALKOXY)- PHENYLACETAMIDES (l) ot-Methoxyphenylacetonitrile.A solution of7.5 g. of a-methoxy-a-phenylacetamide in 30 ml. of thionyl chloride wasrefluxed for two hours and distilled to yield 3.9 g. ofa-methoxy-et-phenylacetonitrile, B.P. 120-123 C. at 19 mm.

(2) a Methoxy-3-trifluoromethylphenylacetonitrile. 2.5 g., B.P. 115120C. at 17 mm., was prepared as in Example E-l using 4 g. oftx-methoxy-3-trifiuoromethylphenylacetamide and 20 ml. of thionylchloride.

(3) a-n-butoxyphenylacetonitrile.4.9 g., B.P. 146- 148 C. at 16 mm., wasprepared as in Example E-l using 7 g. of u-n-butoxy-a-phenylacetamideand 20 ml. of thionyl chloride.

(4) 4 chloro-a-methoxyphenylacetonitrile-B.P. 99- 103 C. at 0.7 mm., wasprepared in 59% yield by dehydration ofa-methoxy-a-4-chlorophenylacetamide by heating it with thionyl chloridein benzene until the theoretical quantity of water was removed.

u-Ethoxyphenylacetonitrile.-B.l. 10l-l06 C. at 0.4 mm., was prepared asin Example -4 in 73% yield Cir 12 by heating ot-ethoxyphenylacetamidewith thionyl chloride in benzene.

(F) OTHER Z-(LOWER-ALKOXY)-2-P HENYL- ALKANENITRILES (1)2-ethoxy-2-phenylbutanenitrile.To a stirred solution of 32.2 g. ofa-ethoxyphenylacetonitrile in 100 ml. of tetrahydrofuran, kept at about510 C. using an ice bath, was added dropwise under nitrogen 27 g. ofpotassium tertiary-butoxide as a 10% w./v. solution in tetrahydrofuran.After the addition, which took thirty minutes, the reaction mixture wasstirred an additional fifteen minutes in ice; the ice bath was removedand the mixture stirred an additional fifteen minutes. To the reactionmixture kept at about 1520 C. was added dropwise over a period of aboutfifteen minutes 39 g. of ethyl iodide. The ice bath was removed and thereaction mixture stirred for forty-five minutes. Then enough glacialacetic acid was added until the reaction mixture was no longer basic towet pH paper (about 0.5 ml.). The mixture was then filtered throughsintered glass and the residual salts thoroughly washed with ether. Thecombined washings and filtrate were distilled in vacuo to yield 23.8 g.of 2 ethoxy 2 phenylbutanenitrile, B.P. 1l3114 C. at 12 mm.

(2) 2 (4 chlorophenyl)-2-ethoxybutanenitrile.B.P. 128-l29 C. at 9 mm.,22.3 g., was prepared as in Example F-l by first adding a solution of39.0 g. of 4-chloroa-ethoxyphenylacetonitrile in 30 ml. oftetrahydrofuran dropwise over a period of forty-five minutes to asolution containing 28.0 g. of potassium tertiary-butoxide in 200 ml. oftetrahydrofuran, maintaining the mixture at about 510 C.; stirring themixture with cooling for another hour; then adding dropwise over aperiod of about thirty minutes to the stirred solution cooled to about10 C. a solution of 42.1 g. of ethyl iodide in 20 ml. oftetrahydrofuran; and working up the reaction mixture as in Example F-l.

Following the procedure described above in Example F-l and usingcorresponding molar equivalent quantities of the appropriatea-(lower-alkoxy)phenylacetonitrile and lower-alkyl or lower-alkenylhalide, the following 2-(lower alkoxy) 2 phenylalkanenitriles areobtained: 2-ethoxy 2 phenylpropanenitrile usingtat-ethoxyphenylacetonitrile and methyl iodide; 2-(4-chlorophenyl)-2-ethoxypentanenitrile using 4-chloro-tat-ethoxyphenylacetonitrile andn-propyl iodide; 2-(3-chlorophenyl)-2-ethoxyhexanenitrile using 3-chloroa ethoxyphenylacetonitrile and n-butyl bromide; 2 ethoxy 2phenyloctanenitrile using a-ethoxyphenylacetonitrile and n-hexylbromide; and, 2-ethoxy 2 (3-fiuorophenyl)-4-pentenenitrile usinga-ethoxy-3fluorophenylacetonitrile and allyl bromide.

(G) 2- [ALPHA- (LOWER-ALKOXY) -BENZYL Z-IMIDAZOLINES (l)2-(a-ethoxybenzyl)-2-imidazoline.-To a mixture containing 16.1 g. ofa-ethoxyphenylacetonitrile and 7.2 g. of ethylenediamine(1,2-ethanediamine) was added five drops of carbon disulfide and thereaction mixture was heated at -99 C. for six hours and then allowed tocool whereupon the reaction mixture solidified. The reaction mixture wastaken up with benzene-isopropyl alcohol (5:1 v./v.). The resultingsolution was filtered, the filtrate concentrated and n-hexane added tocloudiness. The solution was allowed to cool to room temperature and thewalls of the glass container scratched with a glass rod. The resultingcrystalline precipitate was collected and recrystallized once frombenzene and once from methylene chloride-ether to yield 7.5 g. of2-(aethoxybenzyl)- Z-imidazoline, M.P. l23.0-l25.4 C. (corn).

(2) 2-(u ethoxybenzyl)-5-methyl-2-imidazoline.6.6 g., M.P. 102.0-105.6C. (corn), was prepared as in Example G-l using 16.1 g. ofa-ethoxyphenylacetonitrile,

13 8.9 g. of 1,2-prpanediamine and five drops of carbon disulfide, andrecrystallizing once from benzene-n-hexane and once from methylenechloride-n-hexane.

(3) 2-(2,6 dichloro-u-ethoxybenzyl)-2-imidazoline.- To a mixturecontaining 11.5 g. of 2,6-dichlorophenylvc-ethoxyacetonitrile and 6 'g.of ethylenediamine was added three drops of carbon disulfide andresulting mixture was heated with stirring under an atmosphere ofnitrogen at about 130-135 C. for eighteen hours. The reaction mixturewas taken up with a mixture of benzene and water; the benzene layer wasseparated, washed three times with water and then extracted with three50 ml. portions of 2 N hydrogen chloride. The acidic solution was washedwith ether and then made basic with 35% aqueous sodium hydroxidesolution. The separated solid was extracted with benzene and the benzeneremoved by distilling in vacuo. The resulting solid was dissolved in hottetrahydrofuran, the hot solution treated with decolorizing charcoal andfiltered, and the filtrate concentrated and n-hexane added to theconcentrate. The solution was allowed to cool and the resultingprecipitate was collected to yield 7.5 g. of2-(2,6-dichloro-ot-ethoxybenzyl)-2-imidazoline, M.P. 104107 C.

(4) 2-(2 chloro-u-ethoxybenzyl)-2-imidazoline.-12.2 g., M.P. 84-87 C.,was prepared as in Example G-3 using 19.6 g. of2-chloro-ot-ethoxyphenylacetonitrile, 8 g. of ethylenediamine, threedrops of carbon disulfide and a heating period of twelve hours on asteam bath. In the work-up, the reaction mixture was taken up with 1:1(v./v.) benzene-ether and water, and the aqueous layer was extractedwith ether. The combined organic extracts were washed with brine andextracted three times with 2 N hydrogen chloride. The acidic extract wasextracted with ether and then made strongly basic with 35% aqueoussodium hydroxide solution. The basic mixture was extracted three timeswith ether. The ether extract was washed with brine, dried overanhydrous potassium carbonate and evaporated to yield a solid, whichrecrystallized from benzene-n-hexane and dried at 40 C. in vacuo toyield said product.

(5) 2-(3,4 dichloro 0c ethoxybenzyl)-4,4(or 5,5dimethyl-2-imidazoline.To a mixture containing 23.0 g. of3,4-dichlorophenyl-a-ethoxyacetonitrile and 10.6 g. ofZ-methyl-1,2-propanediamine was added five drops of carbon disulfide andthe resulting mixture was heated under an atmosphere of nitrogen at 140C. for about eighteen hours. The reaction mixture was allowed to cooland was poured into benzene. The solution was washed with water and thenextracted with 6 N hydrogen chloride. The acidic extract was madestrongly basic with 35% aqueous sodium hydroxide solution, whilecooling, and the separated basic product was extracted with ether. Theether solution was washed successively with water and brine, dried overanhydrous magnesium sulfate and then concentrated in vacuo to yield asolid. The solid was dissolved in boiling n-hexane. The hexane solutionwas treated with decolorizing charcoal, filtered, concentrated to avolume of about 200 ml. and allowed to cool. The separated solid wascollected, washed with n-hexane and dried at 60 C. for about twenty-sixhours. There was thus obtained 18.2 g. of2-(3,4-dichloro-ot-ethoxybenzy1)- 4,4(or 5,5)-dimethyl-2-imidazoline,M.P. 111-114 C.

(6) 2-(a-n-propoxybenzyl)-2-imidazoline.-A mixture containing 17.5 'g.of a-n-propoxyphenylacetonitrile, 7.2 g. of ethylenediamine and fivedrops of carbon disulfide was heated at 140 C. for two and one-halfhours under an atmosphere of nitrogen and allowed to cool whereupon themixture solidified. The solid was dissolved in ethyl acetate and theresulting solution was washed free of ethylenediamine with water andthen extracted with 1:1 (v./v.) hydrochloric acid. The acidic solutionwas made strongly basic with 35 aqueous sodium hydroxide solution andthe liberated basic product was taken up in ethyl acetate. The ethylacetate solution was washed successively with water and brine, driedover anhydrous magnesium sulfate and evaporated in vacuo to remove 14the solvent. The remaining solid was recrystallized from ether usingdecolorizing charcoal and dried in vacuo at 60 C. for eighteen hours toyield 14.0 g. of 2-(a-n-propoxybenzyl)-2-imidazoline, M.P. 82-84 C.

(7) 2-(u-methoxybenzyl)-imidazoline.8.1 g., 79-80 C., was prepared as inExample G-2 using 14.7 g. of ot-methoxyphenylacetonitrile, 7.2 g. ofethylenediamine, five drops of carbon disulfide, a heating period oftwelve hours on a steam bath and two recrystallizations from methylenechloride-n-hexane.

(7a) 2 (or methoxybenzyl) 2. imidazoline.A mixture containing 3.9 g. ofa-methoxyphenylacetonitrile, 1.6 g. of ethylenediamine and approximately0.3 g. of hydrogen sulfide was heated at -115 C. until the evolution ofammonia had ceased (forty-five minutes). The reaction mixture wasallowed to cool and treated with dilute aqueous hydrochloric acid;decolorizing charcoal was added and the mixture filtered. The filtratewas made alkaline with aqueous sodium hydroxide solution and extractedwith ether. The ether extract was distilled in vacuo to yield 1.9 g. of2-(a-methoxybenzyl)-2-imidazoline, B.P. 114-117 C. at 0.25 mm.

(8) 2 (3,4 dichloro a ethoxybenzyl) 2 imidazoline.6.4 g., M.P. 75-76 C.,was repeated as in Example G-l using 14.9 g. of3,4-dichloro-a-ethoxyphenylacetonitrile, 4.7 g. of ethylenediamine, fourdrops of carbon disulfide, a heating period of six hours at about 100C., four recrystallizations from benzene-n-hexane using decolorizingcharcoal the last time and drying in vacuo at 40 C. for several days.

(9) 2 [cc ethoxy (I naphthyl)methyl] 4,4(or 5,5)dimethyl-2-imidazoline.--10.6 g., M.P. 91-93 C., was prepared as inExample G-3 using 21 g. of a-ethoxyl-naphthylacetonitrile, 10.6 g. of2-methyl-l,2-pr0panediamine, five drops of carbon disulfide, a heatingperiod of twenty-four hours, at 140 0, three recrystallizations n-hexaneusing decolorizing charcoal and drying in vacuo overnight at 60 C.

(10) 2 [a methoxy (1 naphthyl)methyl] 2- imidazoline.A mixturecontaining 9.8 g. of a-methoxyl-naphthylacetonitrile, 3.6 g. ofethylenediamine and three drops of carbon disulfide was heated on asteam bath for about fifteen hours. The reaction mixture was allowed tocool to room temperature and then dissolved in isopropyl acetate. Theisopropyl acetate solution was kept overnight at 0 C., and the resultingcrystalline precipitate was collected and the mother liquor was saved.The crystalline precipitate was dried at 60 C. in vacuo for two days toyield 3 g. of 2 -[a-methoxy-(l-naphthyl) methyl]-2-irnidazoline, M.P.85-86 C. A small sample of said crystalline product was treated with asolution of hydrogen chloride and ether followed by evaporation ofsolvent and trituration with acetonitrile whereupon there were obtainedcrystals of 2-[ot-methoxy-(l-naphthyl) methyl]-2-imidazolinehydrochloride. The above mother liquor was then treated with etherealhydrogen chloride and evaporated in vacuo. The remaining residue wastaken up with ml. of boiling acetonitrile and the hot solution filtered.The filtrate was concentrated and seeded while hot with said crystalline2-[ot-methoxy-( l-naphthyl) methyl]-2-imidazoline hydrochloride and thenallowed to cool to room temperature. The resulting crystalline productwas collected, washed with acetonitrile and then recrystallized bydissolving it in 40 ml. of boiling isopropyl alcohol, addingdecolorizing charcoal, filtering while hot, concentrating the filtrateand then adding acetone until crystallization starts. The mixture wasallowed to cool and the crystalline product that separated was collectedand dried in vacuo at 60 C. to yield 3.5 g. of 2-[amethoxy (lnaphthyl)methyl] 2 imidazoline hydrochloride M.P. 235-237 C.

(11) 2 (a ethoxybenzyl) 4,4(or 5,5) dimethyl- 2-imidazoline.-4.7 g.,M.P. 73 C., was prepared as in Example G-3 using 16.1 g. ofa-ethoxyphenylacetonitrile,

12 ml. of Z-methyl-1,2-propanediamine, five drops of carbon disulfideand a heating period of eighteen hours at 130 C. with stirring. Thereaction mixture was taken up with chloroform rather than benzene; theproduct was triturated twice with n-pentane rather than recrystallizingit and was dried at 0.1 mm. at room temperature over phosphoruspentoxide.

(12) 2 cc methoxy 3 trifiuoromethylbenzyl) 2- imidazoline.Into a mixturecontaining 3.7 g. of amethoxy 3 trifiuoromethylphenylacetonitrile and1.2 g. of ethylenediamine was bubbled briefly hydrogen sulfide and themixture was then heated at 100-110 C. for thirty minutes. Fractionationyielded 2.6 g. of Z-(ocmethoxy 3 trifluoromethylbenzyl) 2 imidazoline,B.P. 117119 C. at 0.35 mm. An ether solution of the base treated withhydrogen chloride yielded 2-(a-methoxy- 3 trifiuoromethylbenzyl) 2imidazoline hydrochloride, M.P. 206-208 C., after recrystallization fromisopropyl alcohol-ether.

13) 2 (4 chloro a methoxybenzyl) 2 imidazolidine.-As its hydrochloride,M.P. 194-195 C., was prepared as in Example G-7a using correspondingmolar equivalent quantities of a-methoxy-4-chlorophenylacetoni trile,ethylenediamine and hydrogen sulfide.

(14) 2 (a n butoxybenzyl) 2 imidazoline-As its hydrochloride, 2.5 g.,M.P. 161l62 C. after recrystallization from isopropyl alcohol-ether, wasprepared as in Example G12 using 4.8 g. of a-n-butoxyphenylacetonitrile,1.6 g. of ethylenediamine, a small quantity of hydrogen sulfide and aheating period of 110-115 C. for twenty-five minutes. The compound infree base form melted at 8083 C. after recrystallization from n-heptane.

(15) 2 (a ethoxybenzyl) 1 methyl 2 imidazoline.B.P. 106-110 C. at 0.3mm., was prepared as in Example G12 using corresponding molar equivalentquantities of a-ethoxyphenylacetonitrile, N-methylethylenediamine andhydrogen sulfide.

(16) l n butyl 2 (a ethoxybenzyl) 2 imidazoline.16.0 g., B.P. 100-110 C.at 0.025 mm., was obtained as in Example G3 using 16.1 g. ofa-ethoxyphenylacetonitrile, 17.4 g. of N-n-butylenediamine, four dropsof carbon disulfide and a heating period of fortyeight hours at 140 C.

l7) 2- a-ethoxy-2-methoxybenzyl) -2-imidazoline.A mixture containing10.0 g. of a-ethoxy-2-methoxyphenylacetonitrile, 8 g. of ethylenediamineand four drops of carbon disulfide was heated at 120 C. for sixteenhours. The excess diamine was removed by heating the reaction mixture at100 C. and mm. for one hour. The residue was taken up in ether andfiltered. The ether solution was extracted with three 25 ml. portions of2 N hydrogen chloride and once with brine. The combined aqueous extractsincluding the brine were made basic with aqueous sodium hydroxidesolution while cooling in an ice bath and the resulting mixture wasextracted three times with chloroform. The chloroform extract was driedover anhydrous potassium carbonate, treated with decolorizing charcoaland filtered. The filtrate was evaporated to remove the chloroformthereby yielding 10.5 g. of 2-(a-ethoxy-2-methoxybenzyl)-2-imidazoline.The latter compound was mixed with ml. of 1.0 M phosphoric acid inabsolute ethanol and the resulting mixture was evaporated. Z-propanolwas added and evaporated off to leave a crystalline product which wasrecrystallized from ml. of absolute ethanol using decolorizing charcoalto yield 8.4 g. of 2-(u-ethoxy-2-methoxybenzyl)-2-imidazoline phosphateM.P. 184186 C.

(18) 2-(a-ethoxy on ethylbenzyl)-2-imidazole.-M.P. 9798 C., 4.5 g., wasprepared as in Example G-3 using 9.0 g. of2-ethoxy-2-phenylbutanenitrile, 5.0 g. of ethylenediamine, six drops ofcarbon disulfide and an initial heating period of five hours at 150 C.with stirring. Additional portions of ethylenediamine totaling 3.5 g.were periodically added to the reaction mixture which was heated anadditional one-hundred and ten hours at 16 C. The reaction mixture wasworked up as in Example G3.

Following the procedure described in Example G, e.g., G-3, G5 or G6,using corresponding molar equivalent quantities of the appropriatea-(lower-alkoxy)phenylacetonitrile or2-(lower-alkoxy)-2-phenylalkanenitrile and 1,2-alkanediamine, thefollowing 2-[a-(lower-alkoxy)ben zyl]-2-imidazolines are obtained:

2-(3-fiuoro-a-n-propoxybenzyl)-4,4( or 5,5)-dimethyl-2- imidazolineusing a-ethoxy-3-fiuorophenylacetonitrile andl-methyl-1,2-propanediamine;

2-(a-ethoxy 4 isopropylbenzyl) 1 ethyl-2-imidazoline usinget-ethoxy-4-isopropylphenylacetonitrile and N- ethylethylenediamine;

2- [u-ethyl-a-S-indanylmethyl] -1,4,5-trimethyl-2- imidazoline usingu-ethoxy-5-indanyl-acetonitrile and N-methyl-2,3-butanediamine;

1-n-butyl-2- (a-ethoxy-4-methoxybenzyl)-4,4 (or 5 5dimethyl-2-imidazoline using a-ethoxy-4-methoxyphenylacetonitrile andN'-butyl-2-methyl-1,2-propanediamine;

2-(2,4-dibromo-a-ethoxybenzyl)-N,4,4-trimethyl-2- imidazoline using2,4-dibromo-a-ethoxyphenylacetonitrile andN',2-dimethyl-1,2-propanediamine;

2-(a,3,4-triethoxybenzyl)-1-methyl-2-imidazoline using01,3,4-triethoxyphenylacetonitrile and N-methylethylenediamine;

4-ethyl-2-(a-ethoxy-3 diethylaminobenzyl)-1-isopropyl- 4-methyl 2imidazoline using tx-ethoxy-3-diethylaminophenylacetonitrile andN-isopropyl-2-methyl-1,2- butanediamine;

2-(a-ethoxy3-fluorobenzyl)-4,4,5,5-tetramethyl-2- imidazoline usinga-ethoxy-3-fluorophenylacetonitrile and 2,3-dimethyl-2,3-butanediamine;

2- ot-ethoxy-4-ethylbenzyl -5-ethyl- 1 ,5-dimethyl-2- imidazoline usinga-ethoxy-4-ethylphenylacetonitrile and N-2-dimethyl-1,Z-dibutanediamine;

2-(a-n-butoxy-4-methylmercaptobenzyl)-2-imidazoline usinga-n-butoxy-4-methylmercaptophenylacetonitrile and ethylenediamine;

2- (a-ethoxy-4-methylsulfonylbenzyl) 1 ,4-diethyl-2- imidazoline usingu-ethoxy-4-methylsulfonylphenylacetonitrile andN-ethyl-l,Z-butanediamine;

2- OL- 4-biphenylyl-a-ethoxy -methyl [-2-imidazoline usingu-ethoxy-4-biphenylylacetonitrile and ethylenediamine;

2-(4-chloro-a-n-hexoxybenzyl)-2-imidazoline using 4-chloro-a-n-hexoxyphenylacetonitrile and ethylenediamine;

2-(wethoxy-u-ethylbenzyl)-2-imidaz0line using 2-ethoxy-2-phenylbutanenitrile and ethylenediamine;

2-(a-allyl-a-ethoxy-3-fiuorobenzyl)-2-imidazoline using 2-ethoxy-2-(3-fluorophenyl)-4-pentenenitrile and ethylenediamine; and,

2-(a-ethoxy-a-n-hexylbenzyl) 2 imidazoline using 2-ethoxy-2-phenyloctanenitrile and ethylenediamine.

(H) 2- [ALPHA- (LOWER-ALKOXY -BENZYL] 1,4,5,6-TETRAHYDROPYRIMIDINES (l)2-(a-ethoxybenzyl) 1,4,S,6 tetrahydropyrimidine-To a mixture containing16.1 g. of a-ethoxyphenylacetonitrile and 8.9 g. of 1,3-propanediaminewas added with swirling five drops of carbon disulfide. The resultingreaction mixture was heated on a steam bath with stirring for six hoursand then allowed to stand at room temperature overnight (about fifteenhours), whereupon solidification resulted. The solid was taken up inbenzene and the benzene solution filtered. The filtrate was concentratedand to it was added n-hexane. The resulting crystalline precipitate wascollected, recrystallized from methylene chloride-n-hexane, washed withn-hexane and dried at 50 C. and 20 mm. to yield 12.1 g. ofZ-(a-ethoxybenzyl)-1,4,5,G-tetrahydropyrimidine, M.P. 10l.4103.6 C.(corn). 2-(a-ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine hydrochl ride,M.P. 143-147 C., was prepared by 17 treating a chilled solution of2-(a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine in methanol with asolution of hydrogen chloride in isopropyl alcohol, evaporating off thesolvent, recrystallizing the residue from acetone and drying theresulting salt at 60 C. in vacuo.

- (2) 2- [u-methoxy-( l-naphthyl) methyl]-1,4,5,6-tetrahydropyrimidine.--4.7 g., M.P. 102.5103.5 C., was preparedas in Example H-l using 9.8 g. of a-methoxy-lnaphthylacetonitrile, 8.9g. of 1,3-propanediamine, four drops of carbon disulfide, a heatingperiod of twenty-four hours and successive recrystallizations fromisopropyl acetate and tetrahydrofuran-isopropyl acetate.

(3) 2-(4-ChlOl'O-0t-BthOXYb6I1ZYl) 1,4,5,6 tetrahydropyrimidine.21 g.,M.P. 93-96 C., was prepared as in Example II-1 using 39.1 g. of4-chloro-a-ethoxyphenylacetonitrile, 17.8 g. of 1,3-propanediamine, sixdrops of carbon disulfide and recrystallization from benzene-nhexane.

(4) 2-(2,6-dichloro or ethoxybenzyl)-l,4,5,6-tetrahy dropyrimidine, 3.5g., M.P. 120-123 C., was prepared as in Example H-l using 17.9 g. of2,6-dichloro-ia-ethoxyphenylacetonitrile, 7 g. of 1,3-propanediamine,four drops of carbon disulfide and the following work-up of the reactionmixture. The solid reaction mixture was taken up in a 1 to 1 mixture(v./v.) of ether-benzene plus some water. The organic layer wasseparated, washed three times with water and then extracted with 2 Naqueous hydrogen chloride. The acidic solution was Washed with ether,mixed with ice and made basic with 10% aqueous sodium hydroxidesolution. The crystalline precipitate Was taken up in benzene, thebenzene solution dried over anhydrous potassium carbonate and thenconcentrated in vacuo followed by addition of n-hexane. The resultingcrystalline product was collected and dried in vacuo at 60 C.

(5) 2-[a-ethoxy-(l naphthyl)methyl] 1,4,5,6 tetrahydropyrimidine, 17.2g., M.P., 101*103 C., was prepared as in Example H-4 using 25.2 g. ofot-ethoxy-bnaphthylacetonitrile, 10.8 g. of 1,3-propanediamine, sevendrops of carbon disulfide and a reflux period of three hours. In thework-up, chloroform was used instead of ether-benzene and the productwas recrystallized from n-hexane. 2-[a-ethoxy-(1-naphthyl)methyl]1,4,5,6 tetrahydropyrimidine hydrochloride, M.P. 227229 C., was preparedby treating an anhydrous ether solution of the basic compound with anexcess of anhydrous ethereal hydrogen chloride, recrystallizing the salttwice from acetonitrile using decolorizing charcoal and drying it invacuo at 75 C. for eighteen hours.

(6) Z-(a ethoxy 3 fiuorobenzyl)-1,4,5,6-tetrahydropyrin1idine.13.9 g.,M.P. 92-94 C., was prepared as in Example H-1 using 17.9 g. ofa-ethoxy-3-fluorophenylacetonitrile, 9.0 g. of 1,3-propanediamine, threedrops of carbon disulfide, a heating period of two and one-half hours at140 C. under an atmosphere of nitrogen and recrystallization from etherusing decolorizing charcoal.

(7) 2-(2 chloro a ethoxybenzyl)-l,4,5,6-tetrahydropyrimidine-11.9 g.,M.P. 101104 C., was prepared in Example H-S using 19.6 g.2-chloro-a-ethoxypheny1acetonitrile, g. of 1,3-propanediamine, threedrops of carbon disulfide, a heating period of twelve hours on a steambath, ether in the work-up and recrystallization from benzene-n-hexane.

(8) 2-(u-6th0XY 4 methylbenzyl)-1,4,5,6-tetrahydropyrimidine.8.5 g.,M.P. 7273 C., was prepared as in Example H-S using 17.5 g. ofa-ethoxy-4-methylphenylacetonitrile, 10.1 g. of 1,3-propanediamine,eight drops of carbon disulfide and a heating period of five hours at140 C.

(9) 2-(a-ethoxybenzyl) 1 methyl-1,4,5,6-tetrahydropyrimidine.20.7 g.,B.P. 8795 C. at 0.02 mm., was prepared as in Example H-S using 25.8 g.of a-ethoxyphenylacetonitrile, 19- ml. of N-methyl-l,3-propanediaminefour drops of carbon disulfide and a heating period of twenty six hoursat 130 C. 1

(10) 2-(3,4 dichloro a ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine.-10.0g., M.P. -92 C., was prepared as in Example H-5 using 23.0 g. of3,4-dichloroz-ethoxyphenylacetonitrile, 9.0 g. of 1,3-propanediamine,three drops of carbon disulfide, a heating period of two and onehalfhours at 140 C. under a nitrogen atmosphere, ethyl acetate in thework-up and successive recrystallizations from cyclohexane (withcharcoal), n-hexane (with charcoal) and ether.

(11) 1,4,5,6-tetrahydro 2 (a n propoxybenzyl)pyrimidine.13.8 g., M.P.86.588.5 C., was prepared as in Example H-10 using 17.5 g. ofa-n-propoxyphenylacetonitrile, 9.0 of 1,3-p-ropanediarnine, five dropsof carbon disulfide, a heating period of four hours at 140 C. andrecrystallization from ether using decolorizing charcoal.

(12) 2-[a-ethoxy (2 naphthyl)methyl]-1,4,5,6-tetrahydropyrimidine.9.4g., M.P. -1 17 C., was prepared as in Example H-10 using 10.56 g. ofot-ethoxy-2-naphthylacetonitrile, 4.45 g. of 1,3-propanediamine, twodrops of carbon disulfide, a heating period of five and one-half hoursat 140 C. and recrystallization from cyclohexane using decolorizingcharcoal.

(13) 2-(a-ethoxy 4 isopropylbenzyl)-1,4,5,6-tetrahydropyrimidine.11.2g., M.P. 105107.5 C., was prepared as in Example H-lO using 20 g. ofa-ethoxy-4-isopropylphenylacetonitrile, 9 g. of 1,3-propanediamine, fivedrops of carbon disulfide, a heating period of five hours at 140 C. andrecrystallization from acetonitrile using decolorizing charcoal.

(14) Z-(oz n butoxybenzyl)-1,4,5,6-tetrahydropyrimidine.--16.7 g., M.P.54-62 C., was prepared as in Example H-10 using 18.9 g. ofan-butoxyphenylacetonitrile, 9.0 g. of 1,3-propanediamine, three dropsof carbon disulfide and a heating period of four hours at 140 C. Thelight yellow waxy product, which was not recrystallized, was dried atroom temperature and 0.03 mm. for fortyfour hours.

(15) 2-[u-ethoxy (5 indanyl)methyl -1,4,5,6-tetrahydropyrimidine.--To amixture containing 20.1 g. of u-ethoxy-S-indanylacetonitrile and 9 g. of1,3-propanediamine was added three drops of carbon disulfide and theresulting mixture was stirred under nitrogen at 140 C. for four andone-half hours. The volatile liquids were evaporated off at 100 C. and15 mm. over a fifteen minute period on a rotary evaporator and theresidue was diluted with benzene. The benzene solution was washed withbrine and extracted with three 100 ml. portions of 2 N aqueous hydrogenchloride. The acidic solution was washed with ether and treatedsuccessively with ice and excess 10% aqueous sodium hydroxide solution.The basic solution was extracted with chloroform. The chloroformsolution was dried over anhydrous potassium carbonate and evaporated toremove the chloroform. The residue was taken up in ether and the ethersolution treated with decolorizing charcoal. The filtrate wasconcentrated and treated with n-hexane and to cloudiness and the mixturestirred at 0 C. The separated product was collected, washed withn-hexane and dried in vacuo at 50 C. to yield 15.2 g. of2-[ix-ethoxy-(S-indanyl)methyl-1,4,5,6- tetrahydropyrimidine, M.P. 69-75C.

(16) 2 (a ethoxybenzyl) l,4,5,6-tetrahydro-5,5-dimethylpyrimidine.24.8g., M.P. 9294 C., was prepared as in Example H-l using 23.5 g. ofa-ethoxyphenylacetonitrile, 16 g. of 2,2 dimethyl-1,3-propanediamine,four drops of carbon disulfide, a heating period of six hours at 135140C. under an atmosphere of nitrogen, hot n-hexane to dissolve the cooledsolid reaction mixture and recrystallization from n-hexane usingdecolorizing charcoal. A solution containing 4 g. ofZ-(a-ethoxybenzyl)-1,4,5,6-tetrahydro-5,S-dimethylpyrimidine in 100 ml.of isopropyl alcohol was treated with 5 ml. of concentrated hydrochloricacid and the resulting solution evaporated to dryness. The solid residuewas recrystallized from 60 ml. of acetone to yield 3.9 g. of2-(a-ethoxy- 19 benzyl)-1,4,5,6-tetrahydro-5,S-dimethylpyrimidinehydrochloride, M.P. 181-183 C.

17) 1 n-butyl-2-(a-ethoxybenzyl)-1,4,5,6-tetrahydr0- pyrimidine.17.5 g.,B.P. 103-110 C. at 0.0075-0.0l mm., was prepared as in Example H- using16.1 g. of ot-ethoxyphenylacetonitrile, 13.0 g. ofN-n-butyl-l,3-propanediamine, four drops of carbon disulfide and etherin the work-up.

(18) 2 (4 chloro-a-ethoxybenzyl)-5-ethyl-1,4,5,6-tetrahydro-5-methylpyrimidine.5.6 g., M.P. 8687 C., was prepared as inExample H-16 using 15.6 g. of 4-chloro-a-ethoxyphenylacetonitrile, 10.2g. of 2-ethyl-2-methyl- 1,3-propanediamine, four drops of carbondisulfide, a heating period of seventeen hours at 135140 C. and threerecrystallizations from n-hexane.

(l9) 2 (4-chloro-a-ethoxybenzyl)-l,4,5,6-tetrahydro- 5,5dimethylpyrimidine, 11.5 g., M.P. l141l5 C., was prepared as in ExampleH-16 using 19.6 g. of 4-chloro-aethoxyphenylacetonitrile, 11.2 g. of 2,2dimethyl-l,3- propanediamine, four drops of carbon disulfide, a heatingperiod of seventeen hours at 135 C. and two recrystallizations fromether-n-hexane.

(20) 2 (2-chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine.11.1 g., M.P. 115ll6 C., was prepared as inExample H-4 using 19.6 g. of 2-chloro-aethoxyphenylacetonitrile, 11.2 g.of 2,2-dimethyl-1,3-propanediamine, four drops of carbon disulfide, aheating period of 135440 C. for seventeen hours, ether in the work-upand recrystallization from ether-n-hexane.

(21) 2 (a-ethoxybenzyl)-5-ethyl-l,4,5,6-tetrahydro-5- methylpyrimidine,12.5 g., B.P. l32135 C. at 0.15 mm., was prepared as in Example H-16using 12.9 g. of aethoxyphenylacetonitrile, 10.2 g. of2-ethyl-2-methyl-l,3- propanediamine, four drops of carbon disulfide, aheating period of seventeen hours at 135-140 C. and then distilling thereaction mixture under vacuum to yield said product.

(22) 2(a-ethoxy-4-isopropylbenzyl)-l,4,5,6-tetrahydro-S,S-dimethylpyrimidine.-14.5g., B.P. 137l39 C. at 0.045 mm., was prepared as in Example H-20 using20.3 g. of a-ethoxy-4-isopropylphenylacetonitrile, 11.2 g. of2,2-dimethyl-1,3-propanediamine, four drops of carbon disulfide, aheating period of seventeen hours at 135140 C., ether in the work-up anddistilling said product under vacuum.

(23) 2 (aethoxy-4-methoxybenzyl)-1,4,5,6-tetrahydro-S,5-dimethylpyrimidine.l0.4g., B.P. l38l43 C. at 0.02 mm., was prepared as in Example H-22 using19.1 g. of a-ethoxy-4-methoxyphenylacetonitrile, 11.2 g. of 2,2-dimethyl-1,3-propanediamine, four drops of carbon disulfide and areaction period of six hours at 132-135 C.

(24) 2 (3-fluoro-a-ethoxybenzyl)-l,4,5,6-tetrahydro- 5,5dimethylpyrimidine.-7.0 g., M.P. 8889 C., was prepared as in Example H4using 17.9 g. of a-ethoxy-3- fiuorophenylacetonitrile, 11.2 g. of2,2-dimethyl-l,3-propanediamine, four drops of carbon disulfide, aheating period of seventeen hours at 130 C., benzene in the work-up andtwo recrystallizations from n-hexane using decolorizing charcoal.

(25) 2 [a-ethoxy(l-naphthyl)methyl]-l,4,5,6-tetrahydro-5,5-methylpyrimidine.5.4 g., M.P.l06l07 C., was prepared as in Example H-16 using 21.1 g. ofaethoxy-l-naphthylacetonitrile, 11.2 g. of 2,2-dimethyl-l,3propanediamine, five drops of carbon disulfide, a heating period of fivehours at 135l40 C., and successive recrystalization from ether-n-hexaneaqueous methanol and n-hexane.

(26) 2 (cc ethoxybenzyl)-1,4,5,6-tetrahydo-5-pyrimidinol, 9.4 g., B.P.148-150 C., at 0.01 mm., was prepared as in Example H-2l using 16.1 g.of a-ethoxyphenylacetonitrile, 10.8 g. of 2-hydroxy-1,3-propanediamine,four drops of carbon disulfide, a heating period of fifteen hours on asteam bath and distillation of said product under vacuum. 2(a-ethoxybenzyl)-l,4,5,6-tetrahydro-5- pyrimidinol hydrochloride, M.P.152l56 C., was prepared by treating an ethanolic solution of the basicproduct with etheral hydrogen chloride, collecting the hydrochloride andtriturating it with acetone and then recrystallizing it twice fromether-acetone.

(27) 2 (a ethoxy-ot-ethylbenzyl)-l,4,5,6-tetrahydropyrimidine, 20.9 g.,M.P. 78.581.0 C., was prepared as in Example H-4 using 23.8 g. ofa-ethoxy-a-phenylbutyronitrile (2-ethoxy-2-phenylbutanenitrile), 11 g.of 1,3-propanediamine, four drops of carbon disulfide, and a heatingperiod of twenty hours at 165 C., ether in the work-up andrecrystallization from n-hexane.

-(28) 2 [a methoxy (4-biphenyl)mcthyl]-l,4,5,6- tetrahydropyrimidine,was prepared as follows: Amixture containing 16.5 g. of OL-mCthQXY4-biphenylacetic acid, 7.4 g. of 1,3-propanediamine and 500 ml. ofxylene was stirred under reflux with a continuous water separatorattached to the reaction vessel. The heating was continued for fourteenhours at which time 3.8 ml. of water had been collected. The reactionmixture was allowed to cool while stirring and then filtered. Thefiltrate was washed successively with water and 10% aqueous potassiumcarbonate solution, and then acidified with aqueous hydrochloric acid.The organic layer was separated and extracted three times with 2 Naqueous hydrogen chloride. The acidic extract was extracted with etherand then made basic with aqueous sodium hydroxide solution. The basicsolution was extracted with chloroform; the chloroform solution wasdried over anhydrous potassium carbonate and then evaporated in vacuo.The residue was crystallized from isopropyl acetate-n-hexane and driedin vacuo at 50 C. to yield 3.8 g. of2-[tx-methoxy-(4-biphenylyl)methyl]- l,4,5,6-tetrahydropyrimidine, M.P.108ll0 C.

(29) 2-(ot-ethoxy-4-methoxyl)-1,4,5,6-tetrahydropyrimidine, 10.64 g.,B.P. -145 C. at 0.06 mm. and M.P. 5256 C., was prepared as in ExampleH-2l using 19.1 g. of a-ethoxy-4-methoxyphenylacetonitrile, 9.0 g. of1,3- propanediamine, five drops of carbon disulfide and a heating periodof six hours at C.

(30) 2 (a methoxybenzyl) 1,4,5,6 tetrahydropyrimidineI-Iydrogen sulfidewas bubbled through a mixture containing 6.4 g. ofa-methoxyphenylacetonitrile and 3.7 g. of 1,3-propanediamine. Theensuing reaction, from which ammonia was evolved, was vigorous andcooling was necessary to control it. After the initial reaction hadsubsided, the mixture was heated at 95 for fifteen minutes, cooled andtreated with dilute aqueous hydrochloric acid. The resulting aqueoussolution was clarified by extraction with ether, after which it was madealkaline and extracted with ether. The ether was distilled off and theresidue distilled in vacuo to yield 5.3 g. ofZ-(a-methoxybenzyl)-l,4,5,6-tetrahydropyrimidine, B.P. 128-129 C. at 0.4mm. and M.P. 6668 C. Treatment of an ether solution of this basiccompound with ethereal hydrogen chloride yielded2-(u-methoxybenzyl)-1,4,5,6-tetrahydropyrimidine hydrochloride, M.P.207208 C. after recrystallization from isopropyl alcohol-ether.

(31) 2 (3 chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine-93 g.,M.P. 8687 C., was prepared as in Example H-4 using 19.6 g. of3-chloro-a-ethoxyphenylacetonitrile, 8.2 g. of 1,3-propanediamine, fourdrops of carbon disulfide, a reaction period of three hours at 135- C.,ether in the work-up and two recrystallizations from n-hexane usingdecolorizing charcoal during the first recrystallization.

(32) 2 (4 chloro-a-ethoxybenzyn-l .4,5,6-tetrahydro-5-methylpyrimidine.4.3 g., M.P. 80-81 C., was prepared as in Example Hl6using 196 g. of 4-Cl'll0I'O-aethoxyphenylacetonitrile, 10.0 g. of2-methyl-l,3-propanediamine, five drops of carbon disulfide, a heatingperiod of six and one-half hours at l36140 C. and recrystallizing thecooled reaction mixture several times from n-hexane using decolorizingcharcoal during the first recrystallization.

(33) 2 (a ethoxybenzyl )-l ,4,5,6-tetralrydro-S-melhyl' pyrimidine-5.5g., M.P. 9798 C., was prepared as in 21 Example H- using 16.1 g. ofa-ethoxyphenylacetonitrile, g. of 2-methyl-1,3-propanediamine, fivedrops of carbon disulfide, a heating period of five hours at 135-140 C.under nitrogen, ether in the work-up and three recrystallizations fromn-hexane using decolorizing charcoal the first time.

(34) 2 (a ethoxybenzyl) 1,4,5,6 tetrahydro 5- methoxypyrimidine.7.3 g.,B.P. 140-146" C. at 0.10- 0.11 mm. (solidified to a waxy solid of M.P.6369 C.), was prepared as in Example H5 using 13.4 g. ofaethoxyphenylacetonitrile, 9.2 g. of 2-methoxy-l,3-propanediamine, sixdrops of carbon disulfide, a heating period of eight hours at 138-140 C.under nitrogen and ether in the work-up.

(3 5) 2- (a-ethoxy-2-methoxybenzyl) -1,4,5,6-tetrahydropyrimidine, 9.4g., M.P. 80-82 C., was prepared as in Example H-4 using 19.1 g. ofa-ethoxy-2-methoxyphenylacetonitrile, 10 g. of 1,3-propanediamine, fivedrops of carbon disulfide, a heating period of eighteen hours at 135-l45C. and recrystallization from n-hexane.

(36) 2 (or ethoxybenzyl) 5,5-diethyl-1,4,5,6-tetrahydropyrimidine, B.P.130-134 C. at 0.03 mm., 12.1 g., was prepared as in Example H-4 using16.1 g. of uethoxyphenylacetonitrile, 14.3 g. of2,2-diethyl-1,3-propanediamine, 6 drops of carbon disulfide and aheating period of twenty-one hours at 130-135 C. under nitrogen. Etherwas used in the work-up and the product was distilled under reducedpressure.

(37) 2 (4 chloro a-EthOXY-u-ethYlbCnZYD-l,4,5,6- tetrahydro 5,5dimethylpyrimidine.-M.P. 124125 C., 4.52 g., was prepared as in ExampleI-I- using 22.3 g. of 2-(4-chlorophenyl)-2-ethoxybutanenitrile, 12.2 g.of 2,2- dimethyl-1,3-propanediamine, six drops of carbon disulfide andinitially a heating period of seventeen hours at 150- 152 C. Additionalportions of carbon disulfide (total of 35 drops) and2,2-diethyl-1,3-propanediamine (total of 7.5 g.) were added to thereaction mixture which was heated an additional seven days at about 175C. Ether was used in the work-up and the product was recrystallized fromn-hexane using decolorizing charcoal.

(38) 2 (4 chloro a ethoxybenzyl)-5,5-diethyl-1,4,5,6-tetrahydropyrimidine.To a mixture containing 19.6 g. of4-chloro-a-ethoxyphenylacetonitrile and 14.3 g. of2,2-diethyl-1,3-propanediamine was added with stirring under anatmosphere of nitrogen, six drops of carbon disulfide and the resultingmixture was stirred under an atmosphere of nitrogen while heating at130-140 C. for seventeen hours. The reaction mixture was then distilledunder reduced pressure to distill off any low boiling diamineintermediate and was then dissolved in 500 ml. of ether. The ether wasextracted with two 500 ml. portions of 6 N hydrochloric acid. The acidicextract was washed with ether, made basic with 35% aqueous sodiumhydroxide solution and the mixture extracted thoroughly with ether. Theether extract was dried over anhydrous sodium sulfate, distilled invacuo to remove the ether and then distilled in vacuo to yield 12.2 g.of 2-(4-chloro-uethoxybenzyl) 5,5 diethyl-1,4,5,6tetrahydropyrimidine,B.P. 148150 C. at 0.02 mm. The product solidified on standing at roomtemperature, and was then recrystallized from n-hexane, usingdecolorizing charcoal, to yield 7.9 g. of white crystalline 2(4-chloro-a-ethoxybenzyl)-5,5-diethyl-1,4,5,6-tetrahydropyrimidine, M.P.68-70 C. after drying in vacuo for twenty-four hours at C.

(39) 2-(4 benzyloxy on ethoxybenzyl) 1,4,5,6- tetrahydropyrimidine.Amixture containing 28.7 g. of a-4-benzyloxy-a-ethoxyphenylacetonitrile,11 g. of 1,3- propane diamine and four drops of carbon disulfide washeated with stirring at 100-110 C. for sixteen hours. The reactionmixture was poured into water and a 1 to 1 mixture (by volume) of etherand benzene. The organic layer was separated, washed with water andextracted three times with 2 N hydrochloric acid. Excess aqueous sodiumhydroxide solution was added with cooling to the aqueous phase and thealkaline mixture was extracted three times with chloroform. Thechloroform extract was dried over anhydrous potassium carbonate whiletreating with decolorizing charcoal, filtered and evaporated in vacuo toremove the chlorofrom, thereby yielding 31.9 g. of2-(4-benzyloxy-a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine.

(40) 2 (a ethoxy 4 hydroxybenzyl) 1,4,5,6- tetrahydropyrimidine.Asolution containing 9.7 g. of 2-(4 benzyloxy oz ethoxybenzyl) 1,4,5,6tetrahydropyrimidine in 250 ml. of absolute ethanol was mixed with 25ml. of 5.6 N hydrogen chloride in absolute ethanol and the resultingmixture was refluxed for fifteen minutes and then evaporated in vacuo toremove the ethanol. The residue, at foamy material, was taken up with 50ml. of 5.6 N hydrochloric acid in absolute ethanol; the mixture wasrefluxed for an additional one hour and forty-five minutes andevaporated in vacuo to remove the ethanol. After examination of thenuclear magnetic resonance spectrum of the residue had indicated onlyabout 50% debenzylation of the starting material, the residue was takenup in ml. of methanol, 600 mg. of 60% palladium chloride was added andthe mixture hydrogenated at 40 p.s.i. for eight hours at roomtemperature. The reaction mixture was filtered and the filtrateevaporated in vacuo to remove the solvent to leave 5.8 g. of 2-(a ethoxy4 hydroxybenzyl) 1,4,5,6 tetrahydropyrimidine as its hydrochloride, anamorphorus white solid.

(41) 2 [a ethoxy 2(and 4)-nitrobenzyl] 1,4,5,6- tetrahydropyrimidine.A5.0 g. portion of 2-(a-ethoxybenzyl) 1,4,5,6 tetrahydropyrimidinehydrochloride was added with swirling and cooling to 25 ml. ofconcentrated sulfuric acid. The acidic solution was cooled to about 05C. and 5 ml. of fuming nitric acid was added slowly with swirlingwhereupon the temperature rose to about 18 C. The reaction mixture wascooled in an ice bath for two hours, poured onto ice and made basic witha slight excess of 35 aqueous sodium hydroxide solution. The alkalinesolution was extracted with chloroform; the extract dried over anhydrouspotassium carbonate while treating with decolorizing charcoal, filteredand evaporated in vacuo to remove the chloroform. The oily residue wasdissolved in isopropyl alcohol and the solution treated with 10 ml. of5.6 N hydrogen chloride in ethanol and the solvents removed bydistilling in vacuo. Isopropyl alcohol was added to the residue and thenremoved by distilling in vacuo. The residue was crystal lized fromacetone-ether, then recrystallized from acetonitrile-acetone and driedin vacuo at 50 C. to yield 1.5 g. of a mixture of2-(a-ethoxy-2-nitrobenzyl) 1,4,5,6- tetrahydropyrimidine hydrochlorideand 2 (a -ethoxy 4- nitrobenzyl) 1,4,5,6 tetrahydropyrimidinehydrochloride, M.P. 202208 C. The nuclear magnetic resonance spectrumindicates the mixture to consist of about 80% of the 2-nitro compoundand about 20% of the 4-nitro compound.

(42) 2 (oz ethoxy 1,4,5,6 tetrahydrobenzyl)- 1,4,5 ,6tetrahydropyrimidine.To a stirred mixture containing 24 g. ofu-ethoxy3-cyclohexenylacetonitrile, 15 g. of 1,3-propanediamine under anatmosphere of nitrogen was added six drops of carbon disulfide and theresulting mixture heated with stirring under an atmosphere of nitrogenfor forty-four hours at -145 C. The reaction mixture was distilled underreduced pressure to remove any excess diamine and the residual oilymaterial was dissolved in ether. The ether solution was extracted with 2N hydrogen chloride. The acidic extract was washed with ether and thenmade basic with 3 N sodium hydroxide solution and the resulting milkysuspension extracted several times with ether (total of 1000 ml.). Theether extract was dried over anhydrous magnesium sulfate and distilledin vacuo to remove the ether and the residue distilled to yield afraction boiling at 103-105 C. at 0.02 mm. This fraction, whichpartially solidified, was distilled again to yield 10.15 g. of2-(a-ethoxy-1,4,

23 5,6-tetrahydrobenzyl) 1,4,5,G-tetrahydropyrimidine, B.P. 9396 C. at0.0l0.0l8 mm. The product solidified on standing, M.P. 7677 C.

(43) 2 (3 chloro a ethoxybenzyl) 1,4,5,6 tetrahydro 5,5dimethylpyrimidine, M.P. 8283 C., 8.0 g., was prepared as in Example Husing 13.8 g. of 3-chloro a ethoxyphenylacetonitrile, 9.0 g. of2,2-dimethyl-1,3-propanediamine, six drops of carbon disulfide andrecrystallization from n-hexane using decolorizing charcoal.

(44) 2- (3 chloro a ethoxybenzyl) 5,5 diethyl-1,4,5,6-tetrahydropyrimidine.B.P. l36138 C. at 0.012- 0.015 mm., 7.2 g.,was prepared as in Example H-Zl using 13.8 g. of3-chloro-a-ethoxyphenylacetonitrile, 11.7 g. of2,2-diethyl-1,3-propanediamine, six drops of carbon disulfide and threevacuum distillations of the product.

(45) 2 (a ethoxy 3 fiuorobenzyl) 5,5 diethyl-1,4,5,6-tetrahydropyrimidine.-B.P. 124-126 C. at 0.015- 0.030 mm., 8.4g., was prepared as in Example H-2l using 14.0 g. ofot-ethoxy-3-fluorophenylacetonitrile, 11.0 g. of2,2-diethyl-1,3-propanediamine and six drops of carbondisulfide.

(46) 2 (2 amino- 4 chloro a ethoxybenzyl)- 1,4,5,6 tetrahydro 5,5dimethylpyrimidine is prepared by catalytic hydrogenation of an ethanolsolution of 2-(4- chloro-a-ethoxy-2-nitrobenzyl) l,4,5,6 -tetrahydro5,5- dimethylpyrimidine in the presence of two equivalents of hydrogenchloride over 10% palladium on charcoal at three atmospheres of hydrogenat room temperature. After completion of the hydrogenation, the reactionmixture is filtered and the ethanol removed from the filtrate to yieldthe product in the form of its dihydrochloride.

(47) 2 [4 (and 2) amino a ethoxybenzyl] 1,4, 5,6-tetrahydropyrimidine isobtained as in Example H-46 using a corresponding molar equivalentquantity of 2-[aethoxy 2 (and 4) nitrobenzyl] 1,4,5,6tetrahydropyrimidine (from Example H-4l (48) 2(m-ethoxycyclohexylmethyl) 1,4,5,6 tetrahydrobyrimidine.In ahydrogenation vessel was placed 30 ml. of absolute ethanol and l g. ofplatinium dioxide. The dioxide was reduced under hydrogen until uptakewas complete. To the platinium suspension was added a solutioncontaining 4.0 g. of 2-(a-ethoxy-l,4,5,6-tetrahydrobenzy1)-l,4,5,6tetrahydropyrimidine, 30 ml. of ethanol and 5 ml. of 4.9 N ethanolichydrogen chloride, thereby yielding a mixture having a pH of 2.Hydrogenation was accomplished at atmospheric pressure and roomtemperature over a period of about six hours. The catalyst was filteredoff through a pad of infusorial earth and the filtrate was distilled at50 C. and 10 mm. to remove the solvents. The remaining oily residue wasdissolved in 10 ml. of ice water and made basic with 20% aqueous sodiumhydroxide solution. The alkaline solution was extracted with ether. Theether extract was dried over anhydrous magnesium sulfate and the etherdistilled off in vacuo. The oily residue was dissolved in 50 ml. ofnhexane, and the solution treated with decolorizing charcoal andfiltered. The filtrate was concentrated to a volume of about 20 ml. andcooled. The crystalline precipitate was collected and dried in vacuo forfour hours to yield 1.82 g. of 2-(a-ethoxycyclohexylmethyl)-1,4,5,6-tetrahydropyrimidine, M.P. 99-100 C.

(49) 2 (a ethoxy 3 fiuoro 4 methoxybenzyl)-1.4,5,6-tetrahydropyrimidinel6.9 g., B.P. 137140 C. at 0.06-0.07 mm.(solidified to a waxy solid of M.P. 77 79 C.), was prepared as inExample H-4 using 14.7 g. of a ethoxy 3 fiuoro 4methoxyphenylacetonitrile, 6.0 g. of 1,3-propanediamine, six drops ofcarbon disulfide and a heating period of seventeen hours.

(50) 2 (oz ethoxy 3 fiuoro 4 methoxybenzyl)- 1,4,5,6 tetrahydro 5,5dimethylpyrimidine.l6.2 g., B.P. 148149 C. at 0.07-0.08 mm. (solidified,M.P. 83-85 C.), was prepared as in Example H-4 using 20.9 g. ofa-ethoxy-3-fiuoro-4-methoxyphenylacetonitrile, 1l.2 g. of 2,2 dimethyl1,3 propanediamine, six

lit

drops of carbon disulfide and a heating period of twenty hours.

Following the procedure described in Example H, e.g., H1, H-4, H-lO orH-16, using corresponding molar equivalent quantities of the appropriatea-(lowcr-alkoxy)- phenylacetonitrile or2-(lower-alkoxy)-2-phenylalkanenitrile and 1,3-alkanediamine, thefollowing 2-[a-(loweralkoxy)-benzyl]-l,4,5,6 tetrahydropyrimidines areobtained:

2-(3-chloro-ot-ethoxybenzyl)-1,4,5,6-tetramethyl-l,4,5,6-

tetrahydropyrimidine using 3-chloro-a-ethoxyphenylacetonitrile andN',2-dimethyl-2,4-pentanediamine;

2-(2-chloro-a,4-diethoxybenzyl)-4,6-dimethy1-1,4,5,6-tetrahydropyrimidine using 2-chloro-a-4-diethoxyphenylacetonitrile and2,4-pentanediamine;

2-(2,4-dibromo-a-ethoxybenzyl -4 (or 6) -ethyl-5-methyl-1,4,5,6-tetrahydropyrimidine using 2,4-dibromo-aethoxyphenylacetonitrileand 2-methyl-1,3-pentanediamine;

2- tx-ethoxy-4-dimethylaminobenzyl) -5-ethyl-4 (or 6n-propyl-1,4,5,6-tetrahydropyrimidine using (it-ethoxy-4-dimethylaminophenylacetonitrile and 2-methyl-1,3- hexanediamine;

2-(a-ethoxy-3-fiuorobenzyl -l-n-hexy1-l ,4,5,6-tetrahydropyrimidineusing a-ethoxy-3-fiuorophenylacetonitrile andN-n-hexyl-1,3-propanediamine;

2- (ot-ethoxy-4-ethylbenzyl) -5-isobutyl-5-methyl-1,4,5,6-

tetrahydropyrimidine using a-ethoxy-4-ethylphenylacetonitrile and2-isobutyl-2-methyl-1,3-propanediamine;

2- Ot-CthOXY-3 ,4,5-trimethoxybenzyl -5-n-butyl-5-ethyl-1,4,5,6-tetrahydropyrimidine using a-ethoxy-3,4,5-trimethoxyphenylacetonitrile and 2-n-butyl-2-ethyl-1,3- propanediamine;

2-(4-n-butoxy-a-ethoxybenzyl)-5,5-dimethyl-1,4,5,6-

tetrahydropyrimidine using 4-n-blltOXY-OL-CthOXYPhGHYlacetonitrile and2,2-dimethyl-1,3-propanediamine;

2-( a-ethoxy-2,4-dimethylbenzyl-5,5-diethyl-1,4,5,6-tetrahydropyrimidine usinga-ethoxy-2,4-dimethylphenylacetonitrile and2,2-diethyl-1,3-propanediamine;

2- a-ethoxy-4-fiuoro-2-methoxybenzyl-5-methy1-5-npropyl-l,4,5,6-tetrahydropyrimidine using a-ethoxy-5-fiuoro-2-methoxyphenylacetonitrile and 2-methyl-2-n-propyl-1,3-propanediamine;

2-(a-ethoxy-4-methylmercaptobenzy1)-5,5-dimethyl-1,4,

5,6-tetrahydropyrimidine usinga-ethoxy-4-methy1mercaptophenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2- e-ethoxy-2,4,6-trimethylbenzyl) -5-methyll ,4,5 ,6-

tetrahydropyrimidine using ot-ethoXy-2,4,6-trimethylphenylacetonitrileand 2-methyl-l,3-propanediamine;

2- wethoxy-4-n-hexoxybenzyl l ,4,5 ,6-tetrahydropyrimidine usingot-ethoxy-4-n-hexoxyphenylacetonitrilc and 1,3-propanediamine;

2-(a-ethoxy-3,5-diiodobenzyl)-5,5-dimethyl-1,4,5,6-

tetrahydropyrimidine using a-ethoxy-3,S-diiodophenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2-(4-n-butylmercapto-a-ethoxybenzyl)-5,5-dimethyl-1,4,

5,6-tetrahydropyrimidine using4-n-butylmcrcapto-uethoxyphenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2- a-ethoxy-4-methylsulfonylbenzyl) -5 ,5 -dimethyll ,4,

5,6-tetrahydropyrimidine usingtz-ethoxy-4-methylsulfonylphenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2- a-ethoxy-4-ethylsulfonylbenzyl) -5 ,5 -dirnethyll ,4,5

G-tetrahydropyrimidine using ot-eth0xy-4-ethylsulfonylphenylacetonitrile and 2,2-dimethyl-1,3-propanediamine;

2-(m-ethoxy-4-nitrobenzyl)-5,5-dimethyl-1,4,5,6-tetrahydropyrimidineusing a-ethoxy-4-nitrophenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2 (4-amino-a-ethoxybenzyl)-5,5-dimethyl-l,4,5,6-tctrahydropyrimidine wasprepared by treating the corresponding 2(a-ethoxy-4-nitrobenzyl)-5,5-dimethyl-1,4,5,6- tetrahydropyrimidine witha reducing agent effective to reduce nitro groups to amino groups, e.g.,iron and hydrochloric acid or by catalytic hydrogenation in the presenceof two molar equivalents of hydrogen chloride using palladium oncharcoal;

2- a-ethoxy-3 -trifluoromethylbenzyl 5-dimethyl-1,4,-5,6-tetrahydropyrimidine usingot-ethoxy-3-trifiuoromethylphenylacetonitrile and2,2-dimethyl-1,3-propanediamine;

2- (4'ChlOIO'OL'l'l6XOXYb6IlZY1 -5 ,5 -dimethyl- 1 ,4,5,6-tetrahydropyrimidine using 4-chloro-u-n-hexoxyphenylacetonitrile and2,2-dimethyl-1,3-propanediamine; 2-(a-ethoxy-a-methylbenzyl)-1,4,5,6-tetrahydropyrimidine using 2-ethoxy-2-phenylpropanenitrile and1,3- propanediamine; 2-(4-chloro-u-ethoxy-a-n-propylbenzyl)-5-methyl-1,4,

5,6-tetrahydropyrimidine using 2-(4chlorophenyl) 2-ethoxypentanenitrileand 2-methyl-l,3-propanediamine;2-(.u-n-butyl-3-chloro-a-ethoxybenzyl)-5,5-dimethyl-1,4,5,6-tetrahydropyrimidine using 2-(3-chlorophenyl2-ethoxyhexanenitrile and 2,2-dimethyl-1,3-propanediamine;2-(a-allyl-a-ethoXy-3-fluorobenzyl)-1,4,5,6-tetrahydropyrimidine using2-ethoxy-2-(3-fluorophenyl)-4- pentenenitrile and 1,3-propanediamine;2-(u-ethoxy-ot-n-hexylbenzyl)-1,4,5,6-tetrahydropyrimidine usingog-ethoxy-a-phenyloctanenitrile and 1,3- propenediamine;2-(3-chloro-a-ethoxybenzyl)-5-ethyl-5-methyl-1,4,5,6-

tetrahydropyrimidine using 3-chloro-a-ethoxyphenylacetonitrile and2-ethyl-2-methyl-1,3-propanediarnine;

2- a-ethoxy-3-fluorobenzyl) -5-ethyl-5-methyl-l,4,5,6-tetrahydropyrimidine using a-cthoxy-3-fluor0phenylacetonitrile and2-ethyl-2-methyl-1,3-propanediamine;

2- (a-ethoxy-3-fiuoro-4-methoxybenzyl -5-ethyl-5-methyl-1,4,5,6-tetrahydropyrimidine using a-ethoxy-3-fluoro-4-methoxyphenylacetonitrile and 2-ethyl-2-methyl-1,3-propanediarnine;

2- u-ethoxy-3-fluoro-4-methoxybenzyl -5 ,5 -diethyl- 1 ,4,

5,6-tetrahydropyrimidine using u-ethoxy-3-fiuoro-4-methoxyphenylacetonitrile and 2,2-diethyl-l,3-propanediamine;

2- 4-chloro-a-ethoxy-2-nitrobenzyl) -5 ,5 -dimethyl-1 ,4,

5,6-tetrahydropyrimidine using 4-chloro-a-ethoxy-2-nitrophenylacetonitrile and 2,2-dimethyl-1,3-propanediamine.

(I) 2- [ALPHA- (LOWER-ALKOXY) -BENZYL] -4,5, 6,7 -TETRAHYDRO- 1 H- l ,3-DIAZEPINES 1) 2-(u-ethoxybenzyl-4,5,6,7-tetrahydro-1H-1,3diazepine.--To a mixture containing 16.1 g. ofa-ethoxyphenylacetonitrile and 12 ml. of 1,4-butanediamine was addedfive drops of carbon disulfide and the resulting mixture was heatedunder an atmosphere of nitrogen for twenty hours at 110 C. The cooledreaction mixture was dissolved in 200 ml. of chloroform. The chloroformsolution was washed with water, dried over anhydrous sodium sulfate anddistilled in vacuo to remove the chloroform. The residue was thendistilled under reduced pressure to yield 8.8 g. of 2-(a-ethoxybenzyl)-4,5,6,7-tetrahydro-lH-l,3-diazepine, B.P. 1l0ll3 C. at0.06 mm.

(2) 2 (2-chloro-a-ethoxybenzyl)-4,5,6,7-tetrahydro-1H-1,3-diazepine.2l.3 g., B.P. 124-130 C. at 0.05 mm., was prepared asin Example I-1 using 19.6 g. of Z-chloroa-ethoxyphenylacetonitrile, 14ml. of l,4-butanediamine, five drops of carbon disulfide and a heatingperiod of twenty-nine hours on a steam bath under nitrogen. 2-(2-chloro-a-ethoxybenzyl)-4,5,6,7-tetrahydro 1H-1,3 diazepinehydrochloride, M.P. 73-74 C., was prepared by treating an ether solutionof the basic diazepine with ethereal hydrogen chloride and collectingthe precipitated hydrochloride. Similarly, 2 (Z-ChIOIO-a-EthOXYbGlIZYD-4,5,6,7 tetrahydro 1H 1,3-diazepine cyclohexanesulfamate, M.P. 128-l30C., was prepared by treating an acetone solution of the basic diazepinewith an acetone solution of cyclohexanesulfamic acid and collecting theprecipitated cyclohexanesulfamate.

(3) 2 (4 chloro-a-ethoxybenzyl)-4,5,6,7-tetrahydrolH-l,3-diazepine.-33.2g., B.P. 139-l42 C. at 0.03 mm., was prepared as in Example I-l using39.2 g. of 4-chlorowt-ethoxyphenylacetonitrile, 28 ml. of1,4-butanediamine, seven drops of carbon disulfide and a heating periodof thirty-two hours on a steam bath under nitrogen. The distilledproduct on cooling solidified as a white waxy material which melted atabout 39 C.

Following the procedure described in Example I-l using correspondingmolar equivalents of the appropriate ot-(lower-alkoxy)phenylacetonitrileor 2-(lower-alkoxy)- 2-phenylalkanenitrile and 1,4-alkanediamine, thefollowing 2 [a-(lower-alkoxy)-benzyl]-4,5,6,7-tetrahydro-1H- 1,3diazepines are obtained:

2- 3-chloro-a-ethoxybenzyl)-1-methyl-4,5,6,7-tetrahydro-lH-l,3-diazepineusing 3-chloro-a-ethoxyphenylacetonitrile andN-methyl-1,4-butanediamine;

3-(wethoxy-3-fluorobenzyl)-l-isoamyl-4,5,6,7-tetrahydro-lH-l,3-diazepineusing a-ethoxy-3-fluorophenylacetonitrile andN-isoamyl-1,4-butanediamine;

2- 3 ,4-dichloro-a-ethoxybenzyl) 1-ethyl-4-methyl-4,5 ,6,7-tetrahydro-1H-1,3-diazepine using3,4-dichloro-otethoxyphenylacetonitrile and N -ethyl-l,4-pentanediamine;

2-(a-ethoxy-l-naphthylmethyl) -4,5,6,7-tetrahydro-1H- 1,3-diazepineusing a-ethoxy-l-naphthylacetonitrile and 1,4-butanediamine;

2-(a-ethoxy-S-indanylmethyl) -4,5,6,7-tetrahydro-1H- 1,3-diazepine usingu-ethoxy-4-indanylacetonitrile and 1,4-butanediamine;

2- (OC-BthOXy'3 -trifluoromethylb enzyl-4,5 ,6,7-tetrahydro-1H-l,3-diazepine using a-ethoxy-3-trifluoromethylphenylacetonitrile and1,4-butanediamine;

2-(u-ethoxy-4-methylbenzyl)-4,5,6,7-tetrahydro-lH-1,3- diazepine usingu-ethoxy-4-methylphenylacetonitrile and 1,4-butanediamine;

2- a-ethoxy-4-methoxybenzyl -4,5,6,7-tetrahydro-1H- 1,3-diazepine usingu-ethoxy-4-methoxyphenylacetonitrile and 1,4-butanediamine;

2- a-ethoxy-4-dimethylaminobenzyl) -4,5,6,7-tetrahydro 1H-1,3-diazepineusing u-ethoxy-4-dimethylaminophenylacetonitrile and 1,4-butanediamine;

2- u-ethoxy-4-methylmercaptobenzyl) -4,5,6,7-tetrahydro-lH-1,3-diazepineusing a-ethoxy-4-methylmercaptophenylacetonitrile and 1,4-butanediamine;

2- a-ethoxy-4-methylsulfonylbenzyl) -4,5,6,7-tetrahydro-1H-1,3-diazepine using a-ethoxy-4-methylsulfonylphenylacetonitrile and1,4-butanediamine;

2-(a-ethoxyl-nitrobenzyl)-4,5,6,7-tetrahydro-1H-1,3-

diazepine using a-ethoxy-4nitrophenylacetonitrile and 1,4-butanediamine;

2-(a-ethoxy-4-biphenylylmethyl)-4,5,6,7-tetrahydro-1H- 1,3-diazepineusing ot-ethoxy-4-biphenylylacetonitrile and 1,4-butanediamine;

2-(4-chloro-ot-ethoxybenzyl)-4,6(or 5 ,{7)-dimethyl-4,5 ,6,7-tetrahydro-1H-1,3-diazepine using 4-chloro-u-ethoxyphenylacetonitrileand 2-methyl-1,4-pentanediamine;

2- a-ethoxybenzyl) -5 (or6 -methoxy-4,5 ,6,7-tetrahydro-1H-l,3-diazepine using \ot-ethoxyphenylacetonitrile and2-methoxy-1,4-butanediamine.

The anti-inflammatory activity was measured by the inhibition ofcarrageenin-induced local foot edema in fasted rats generally accordingto the procedure of C. A. Winter et al., Proc. Soc. Exptl. & Med. 111,544-547 (1962) as follows: Food is withdrawn from male albino ratsweighing approximately -124 gms., eighteen hours prior to a single oralmedication of the test compound. Each compound is administered to atleast five rats. One hour following the medication, 0.05 ml. of 1%aqueous suspension of carrageenin is injected into the plantar tissue ofthe right hind foot. Three hours after injections, the rats aresacrificed and the hind feet cut off at the tibiocalcaneo-talar joint orsubsequent weighing. The observed difference between the average edemaweight of the control and medicated rats is expressed as percentinhibition of edema. When tested by the above-described procedure, 2[a-(lower-alkoxy)-arylmethyl]2-imidazolines,-1,4,5,6-tetrahydropyrimidines and -4,S,6,7-tetrahydro-lH-l,3-diazepinesof the invention were found to inhibit local edema due tocarrageenin-induced inflammation when administered at oral dose levelsbetween about 6 and 400 mg./kg.

The hypoglycemic activity was measured by the percent decrease in bloodglucose levels from premedicated blood glucose levels in fasted ratsgenerally according to the procedure of Dulin et al., Proc. Soc. Exptl.& Med. 107, 245 (1961), wherein glucose-primed rats were bled from thetail vein at 1, 2, 3 and 5 hours following medication. Hypoglycemicactivity is expressed as the percent decrease in blood glucose from thecontrol animals at the same hour. When tested by this procedure, thecompounds of the invention were found to have hypoglycemic activity whenadministered at oral dose levels between about and 1000 mg./kg.

The diuretic activity was measured by the natriuretic response producedin rats generally according to the procedure of Williamson et al., J.Pharm. & Exptl. Therap. 126, 82 (1959), using male albino rats, 160-200g., which have been fasted overnight. The compound to be tested isadministered orally in 0.5% gum tragacanth in 0.85% NaCl at a volume ofml./l00 g. body weight. The compound is administered to six animals ateach dose level. Twelve control (no drug) animals and six animalstreated with 8 micromolcs/kg. of hydrochlorothiazide are run in eachexperiment. A fixed molar dose schedule for drugs is used. The highestdose used is 50 micromoles/ kg. Succeeding doses are of each precedingdose. Testing of a compound is completed when it no longer produces anatriuretic response which is significantly greater than that of thenon-drug-treated groups. The dose of drug which produces a response 0.50times that of the reference drug, hydrochlorothiazide, is then reportedas the approximate minimal effective dose of the AMED- Na. When testedby the above-described procedure, Z-[oz-(lower-alkoxy)-benzyl]-1,4,5,6-tetrahydropyrimidines and4,5,6,7-tetrahydro 1H 1,3-diazepines of the invention were found to havediuretic activity when administered at oral dose levels between about 2and micromoles/ kg.

The actual determination of the numerical biological data definitive fora particular compound is readily obtained by standard test procedures,referred to above, by technicians versed in pharmacological testprocedures, without any need for any extensive experimentation.

The compounds of Formula I above can be prepared for use by conventionalpharmaceutical procedures: that is, by dissolving or suspending them ina pharmaceutical acceptable vehicle, e.g., aqueous alcohol, glycol, oilsolution, or oil-water emulsion, for parenteral or oral administration;by incorporating them in unit dosage form as tablets or capsules fororal administration either alone or 28 in combination with conventionaladjuvants, e.g., calcium carbonate, starch, lactose, talc, magnesiumstearate, gum acacia, and the like.

The subject matter which the applicant regards as his invention isparticularly pointed out and distinctly claimed as follows:

1. A compound having the formula wherein:

R is lower-alkyl,

R is hydrogen, lower-alkyl or lower-alkenyl,

R is hydrogen or lower-alkyl,

Y is alkylene of 4-8 carbon atoms in which 4 carbon atoms intervenebetween the valence linkages and Ar is phenyl, naphthyl, indanyl,biphenylyl, cyclohexenyl, cyclohexyl and phenyl substituted by from oneto three substituents selected from lower-alkyl, loweralkoxy, halo,trihalomethyl, lower-alkylmercapto, lower-alkylsulfonyl,di(lower-alkyl)amino, amino, hydroxy, nitro and benzyloxy.

2. 2 [on (lower alkoxy Ar-methyl]4,5,6,7-tetrahydro-1H-1,3-diazepineaccording to claim 1 wherein four carbon atoms intervene between thevalence linkages of alkylene.

3. 2 (2 chloro u-ethoxybenzyl)-4,5,6,7-tetrahydrolH-1,3-diazepineaccording to claim 2 where Ar is 2- chlorophenyl, R is ethyl, R and Rare each hydrogen, and Y is CHZCHZCHZCHQ.

4. 2-(a-ethoxybenzyl)-4,5,6,7-tetrahydro-1H-1,3-diazepine according toclaim 2 where Ar is phenyl, R is ethyl, R and R are each hydrogen, and Yis CH CH CH CH 2 (P- y nzyl)-4,5,6,7-tetrah dro-1H- 1,3-diazepineaccording to claim 2 where Ar is 4-chlorophenyl, R is ethyl, R and R areeach hydrogen, and Y is CH CH CH CH References Cited UNITED STATESPATENTS 7/1967 Blater 260251 OTHER REFERENCES ALEX MAZEL, PrimaryExaminer J. A. NARCAVAGE, Assistant Examiner U.S. Cl. X.R.

260-251 R, 256.4 H, 309.6, 465 F, 599, 611 A; 424- 244, 25l, 273

